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PURPOSE: To utilize voxel-based dosimetry following radiation segmentectomy to understand microsphere distribution and validate current literature regarding radiologic and pathologic outcomes. METHODS: A retrospective, single-center analysis of solitary HCC patients (n=56) treated with Y90 radiation segmentectomy with glass microspheres (TheraSphere; Boston Scientific, Marlborough, MA, USA) from 2020 to 2022 was performed. Post-treatment voxel-based dosimetry was evaluated using Mirada DBx Build 1.2.0 Simplicit90Y software and utilized to calculate sphere concentration to tumor, as well as D70 (minimum dose to 70% total tumor volume), D90, and D99. Time to progression (TTP), treatment response, and adverse events were studied. RESULTS: Fifty-six solitary tumors were analyzed with a median tumor diameter of 3.4cm (range 1.2-6.8cm) and median tumor absorbed dose of 732Gy (range, 252-1776Gy). Median sphere activity (SA) at time of delivery was 1446Bq (range, 417-2621Bq). Median tumor sphere concentration was 12,868 spheres/mL (range, 2,655-37,183 spheres/mL). Sphere concentration into tumor and normal tissue inversely correlated with perfused treatment volume (R2=0.21 and 0.39, respectively). Of the 51 tumors with post-treatment imaging, objective response was noted in 49 patients (96%) and complete response in 42 patients (82%). The median TTP was not reached with a 2-year progression rate of 11%. 15 patients underwent liver transplant. Median tumor necrosis was 99% (range, 80-100%). Lower tumor volumes and higher D99 were associated with CPN (p<0.001 and p=0.022, respectively). CONCLUSION: Voxel-based dosimetry following Y90 radioembolization can be utilized to account for sphere deposition and distribution into tumor. Ablative RS with high SA yields durable radiologic and pathologic outcomes.
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BACKGROUND: Evaluating transarterial radioembolization (TARE) in patients with metastatic colorectal carcinoma of the liver who have progressed on first-line chemotherapy (EPOCH) demonstrated superior outcomes using yttrium-90 glass microspheres plus chemotherapy (TARE/Chemo) vs chemotherapy (Chemo) to treat colorectal liver metastases. Additional exploratory analyses were undertaken to assess the impact of TARE/Chemo on efficacy, safety, time to subsequent therapy, time to deterioration in quality of life (QoL), and identify criteria for improved patient selection. METHODS: Time to deterioration in QoL was analyzed for the primary study population. Subsequently, a post hoc analysis was undertaken to identify subgroups for which time to deterioration in QoL was improved with TARE/Chemo vs Chemo. Progression-free survival (PFS), hepatic (h)PFS, time to subsequent therapy, and safety outcomes were compared between treatments. RESULTS: The primary population showed no significant difference in time to deterioration in QoL between treatment arms; however, significance was seen in 2 identified subgroups, namely: Subgroup A (Nâ =â 303) which excluded patients with both Eastern Cooperative Oncology Group (ECOG) 1 and baseline CEAâ ≥â 35 ng/mL from both treatment arms; subgroup B (Nâ =â 168) additionally excluded patients with KRAS (Kirsten rat sarcoma) mutation. In subgroup A, TARE/Chemo patients (Nâ =â 143) demonstrated superior outcomes vs Chemo (Nâ =â 160): PFS (9.4 vs. 7.6 months, hazard ratio (HR): 0.64; 1-sided Pâ =â .0020), hPFS (10.8 vs. 7.6 months, HR: 0.53; 1-sided Pâ <â .0001), time to deterioration in QoL (5.7 vs. 3.9 months, HR: 0.65; 1-sided Pâ =â .0063), and time to subsequent therapy (21.2 vs. 10.5 months, HR: 0.52; 1-sided Pâ <â .0001). Subgroup B patients showed similar but larger significant differences between treatment arms. Median PFS, hPFS, and time to deterioration in QoL were numerically greater for TARE/Chemo in both subgroups vs the primary population, with the greatest magnitude of difference in subgroup B. Both subgroups exhibited higher percentage of CEA responders and improved ORR with TARE/Chemo vs chemo alone. Safety (reported as event rate/100 patient-years) was higher with Chemo in all populations. Additional efficacy analyses in the primary population are also reported. CONCLUSIONS: Careful patient selection, including consideration of the prognostic factors ECOG, baseline CEA, and KRAS status, sets outcome expectations in patients with colorectal liver metastases suitable for TARE/Chemo as second-line treatment (Trial Registry Number: NCT01483027).
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Neoplasias Colorrectales , Neoplasias Hepáticas , Calidad de Vida , Radioisótopos de Itrio , Humanos , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/terapia , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/terapia , Radioisótopos de Itrio/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Selección de Paciente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , VidrioRESUMEN
BACKGROUND: Personalised multi-compartment dosimetry based on [99mTc]Tc-MAA is a valuable tool for planning 90Y radioembolization treatments. The establishment and effective application of dose-effect relationships in yttrium-90 (90Y) radioembolization requires [99mTc]Tc-MAA SPECT quantification ideally independent of clinical site. The purpose of this multi-centre phantom study was to evaluate inter-site variability of [99mTc]Tc-MAA imaging and evaluate a standardised imaging protocol. Data was obtained from the TARGET study, an international, retrospective multi-centre study including 14 sites across 8 countries. The impact of imaging related factors was estimated using a NEMA IQ phantom (representing the liver), and a uniformly filled cylindrical phantom (representing the lungs). Imaging was performed using site-specific protocols and a standardized protocol. In addition, the impact of implementing key image corrections (scatter and attenuation correction) in the site-specific protocols was investigated. Inter-site dosimetry accuracy was evaluated by comparing computed Lung Shunt Fraction (LSF) measured using planar imaging of the cylindrical and NEMA phantom, and contrast recovery coefficient (CRC) measured using SPECT imaging of the NEMA IQ phantom. RESULTS: Regarding the LSF, inter-site variation with planar site-specific protocols was minimal, as determined by comparing computed LSF between sites (interquartile range 9.6-10.1%). A standardised protocol did not improve variation (interquartile range 8.4-9.0%) but did improve mean accuracy compared to the site-specific protocols (5.0% error for standardised protocol vs 8.8% error for site-specific protocols). Regarding the CRC, inter-system variation was notable for site-specific SPECT protocols and could not be improved by the standardised protocol (CRC interquartile range for 37 mm sphere 0.5-0.7 and 0.6-0.8 respectively), however the standardised protocol did improve accuracy of sphere:background determination. Implementation of key image corrections did improve inter-site variation (CRC interquartile range for 37 mm sphere 0.6-0.7). CONCLUSION: Eliminating sources of variability in image corrections between imaging protocols reduces inter-site variation in quantification. A standardised protocol was not able to improve consistency of LSF or CRC but was able to improve accuracy.
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PURPOSE: Investigate reproducibility of two segmentation methods for multicompartment dosimetry, including normal tissue absorbed dose (NTAD) and tumour absorbed dose (TAD), in hepatocellular carcinoma patients treated with yttrium-90 (90Y) glass microspheres. METHODS: TARGET was a retrospective investigation in 209 patients with < 10 tumours per lobe and at least one tumour ≥ 3 cm ± portal vein thrombosis. Dosimetry was compared using two distinct segmentation methods: anatomic (CT/MRI-based) and count threshold-based on pre-procedural 99mTc-MAA SPECT. In a round robin substudy in 20 patients with ≤ 5 unilobar tumours, the inter-observer reproducibility of eight reviewers was evaluated by computing reproducibility coefficient (RDC) of volume and absorbed dose for whole liver, whole liver normal tissue, perfused normal tissue, perfused liver, total perfused tumour, and target lesion. Intra-observer reproducibility was based on second assessments in 10 patients ≥ 2 weeks later. RESULTS: 99mTc-MAA segmentation calculated higher absorbed doses compared to anatomic segmentation (n = 209), 43.9% higher for TAD (95% limits of agreement [LoA]: - 49.0%, 306.2%) and 21.3% for NTAD (95% LoA: - 67.6%, 354.0%). For the round robin substudy (n = 20), inter-observer reproducibility was better for anatomic (RDC range: 1.17 to 3.53) than 99mTc-MAA SPECT segmentation (1.29 to 7.00) and similar between anatomic imaging modalities (CT: 1.09 to 3.56; MRI: 1.24 to 3.50). Inter-observer reproducibility was better for larger volumes. Perfused normal tissue volume RDC was 1.95 by anatomic and 3.19 by 99mTc-MAA SPECT, with corresponding absorbed dose RDC 1.46 and 1.75. Total perfused tumour volume RDC was higher, 2.92 for anatomic and 7.0 by 99mTc-MAA SPECT with corresponding absorbed dose RDC of 1.84 and 2.78. Intra-observer variability was lower for perfused NTAD (range: 14.3 to 19.7 Gy) than total perfused TAD (range: 42.8 to 121.4 Gy). CONCLUSION: Anatomic segmentation-based dosimetry, versus 99mTc-MAA segmentation, results in lower absorbed doses with superior reproducibility. Higher volume compartments, such as normal tissue versus tumour, exhibit improved reproducibility. TRIAL REGISTRATION: NCT03295006.
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Carcinoma Hepatocelular , Embolización Terapéutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/radioterapia , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/tratamiento farmacológico , Estudios Retrospectivos , Reproducibilidad de los Resultados , Agregado de Albúmina Marcado con Tecnecio Tc 99m , Tomografía Computarizada de Emisión de Fotón Único , Radioisótopos de Itrio/uso terapéutico , Microesferas , Embolización Terapéutica/efectos adversosRESUMEN
PURPOSE: In light of recently published clinical reports and trials, the TheraSphere Global Dosimetry Steering Committee (DSC) reconvened to review new data and to update previously published clinical and dosimetric recommendations for the treatment of hepatocellular carcinoma (HCC). METHODS: The TheraSphere Global DSC is comprised of health care providers across multiple disciplines involved in the treatment of HCC with yttrium-90 (Y-90) glass microsphere-based transarterial radioembolization (TARE). Literature published between January 2019 and September 2021 was reviewed, discussed, and adjudicated by the Delphi method. Recommendations included in this updated document incorporate both the results of the literature review and the expert opinion and experience of members of the committee. RESULTS: Committee discussion and consensus led to the expansion of recommendations to apply to five common clinical scenarios in patients with HCC to support more individualized efficacious treatment with Y-90 glass microspheres. Existing clinical scenarios were updated to reflect recent developments in dosimetry approaches and broader treatment paradigms evolving for patients presenting with HCC. CONCLUSION: Updated consensus recommendations are provided to guide clinical and dosimetric approaches for the use of Y-90 glass microsphere TARE in HCC, accounting for disease presentation, tumor biology, and treatment intent.
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Carcinoma Hepatocelular , Embolización Terapéutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Radioisótopos de Itrio/uso terapéutico , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/tratamiento farmacológico , Microesferas , Radiofármacos/uso terapéutico , Embolización Terapéutica/métodos , VidrioRESUMEN
PURPOSE: To investigate the relationships between tumor absorbed dose (TAD) or normal tissue absorbed dose (NTAD) and clinical outcomes in hepatocellular carcinoma (HCC) treated with yttrium-90 glass microspheres. METHODS: TARGET was a retrospective investigation in 13 centers across eight countries. Key inclusion criteria: liver-dominant HCC with or without portal vein thrombosis, < 10 tumors per lobe (at least one ≥ 3 cm), Child-Pugh stage A/B7, BCLC stages A-C, and no prior intra-arterial treatment. Multi-compartment pre-treatment dosimetry was performed retrospectively. Primary endpoint was the relationship between ≥ grade 3 hyperbilirubinemia (such that > 15% of patients experienced an event) without disease progression and NTAD. Secondary endpoints included relationships between (1) objective response (OR) and TAD, (2) overall survival (OS) and TAD, and (3) alpha fetoprotein (AFP) and TAD. RESULTS: No relationship was found between NTAD and ≥ grade 3 hyperbilirubinemia, which occurred in 4.8% of the 209 patients. The mRECIST OR rate over all lesions was 61.7%; for the target (largest) lesion, 70.8%. Responders and non-responders had geometric mean total perfused TADs of 225.5 Gy and 188.3 Gy (p = 0.048). Probability of OR was higher with increasing TAD (p = 0.044). Higher TAD was associated with longer OS (HR per 100 Gy increase = 0.83, 95% CI: 0.71-0.95; p = 0.009). Increased TAD was associated with higher probability of AFP response (p = 0.046 for baseline AFP ≥ 200 ng/mL). CONCLUSION: Real-world data confirmed a significant association between TAD and OR, TAD and OS, and TAD and AFP response. No association was found between ≥ grade 3 hyperbilirubinemia and NTAD. TRIAL REGISTRATION NUMBER: NCT03295006.
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Carcinoma Hepatocelular , Embolización Terapéutica , Neoplasias Hepáticas , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/radioterapia , Embolización Terapéutica/efectos adversos , Humanos , Hiperbilirrubinemia/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/radioterapia , Microesferas , Estudios Retrospectivos , Resultado del Tratamiento , Radioisótopos de Itrio/uso terapéutico , alfa-FetoproteínasRESUMEN
BACKGROUND AND AIMS: Locoregional therapies, including yttrium-90 radioembolization, play an important role in the treatment of unresectable HCC. The aim of the LEGACY (Local radioEmbolization using Glass Microspheres for the Assessment of Tumor Control with Y-90) study was to evaluate objective response rate (ORR) and duration of response (DoR) in patients with solitary unresectable HCC treated with yttrium-90 glass microspheres. APPROACH AND RESULTS: LEGACY is a multicenter, single-arm, retrospective study conducted at three sites that included all eligible, consecutive patients with HCC treated with radioembolization between 2014 and 2017. Eligibility criteria included solitary HCC ≤ 8 cm, Child-Pugh A cirrhosis, and Eastern Cooperative Oncology Group performance status 0-1. Primary endpoints were ORR and DoR based on modified Response Evaluation Criteria in Solid Tumors in the treated area (localized), as evaluated by blinded, independent, central review. Radioembolization was performed with intent of ablative-level dosimetry in a selective fashion when possible. Overall survival was evaluated using Kaplan-Meier and multivariate Cox proportional hazards. Among the 162 patients included, 60.5% were Eastern Cooperative Oncology Group 0, and the median tumor size was 2.7 cm (range: 1-8) according to blinded, independent, central review. Radioembolization served as neoadjuvant therapy for transplantation or resection in 21.0% (34 of 162) and 6.8% (11 of 162) of patients, respectively, and as primary treatment for all others. Median follow-up time was 29.9 months by reverse Kaplan-Meier. ORR (best response) was 88.3% (CI: 82.4-92.4), with 62.2% (CI: 54.1-69.8) exhibiting a DoR ≥ 6 months. Three-year overall survival was 86.6% for all patients and 92.8% for those neoadjuvant patients with resected or transplanted liver. CONCLUSIONS: In this multicenter study of radioembolization, clinical meaningful response rates and prolonged DoR were observed in the treatment of unresectable, solitary HCC ≤ 8 cm.
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Braquiterapia/métodos , Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/radioterapia , Terapia Neoadyuvante/métodos , Radiofármacos/uso terapéutico , Radioisótopos de Itrio/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/cirugía , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/cirugía , Trasplante de Hígado/métodos , Masculino , Microesferas , Persona de Mediana Edad , Radiofármacos/efectos adversos , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven , Radioisótopos de Itrio/efectos adversosRESUMEN
The TheraSphere Global Dosimetry Steering Committee was formed in 2017 by BTG International to review existing data and address gaps in knowledge related to dosimetry. This committee is comprised of health care providers with diverse areas of expertise and perspectives on radiation dosimetry. The goal of these recommendations is to optimize glass microspheres radiation therapy for hepatocellular carcinoma while accounting for variables including disease presentation, tumour vascularity, liver function, and curative/palliative intent. The recommendations aim to unify glass microsphere users behind standardized dosimetry methodology that is simple, reproducible and supported by clinical data, with the overarching goal of improving clinical outcomes and advancing the knowledge of dosimetry.
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Conferencias de Consenso como Asunto , Guías de Práctica Clínica como Asunto , Radiometría/normas , Radiofármacos/normas , Radioterapia/normas , Radioisótopos de Itrio/normas , Carcinoma Hepatocelular/radioterapia , Humanos , Neoplasias Hepáticas/radioterapia , Microesferas , Radiofármacos/uso terapéutico , Radioterapia/métodos , Dosificación Radioterapéutica , Radioisótopos de Itrio/uso terapéuticoRESUMEN
BACKGROUND AND AIMS: OncoGel (Protherics Salt Lake City, Inc, Salt Lake City, UT) is paclitaxel (PTX) formulated in a thermosensitive, biodegradable copolymer for focused cytotoxicity and radiosensitization. A phase 2a study suggested that EUS-guided PTX injection into esophageal tumors subsequently receiving radiotherapy was safe. METHODS: In an international multicenter, prospective, randomized phase 2b study, patients with local or locoregional adenocarcinoma or squamous cell carcinoma (SCC) of the esophagus/gastroesophageal junction and eligible for neoadjuvant chemoradiotherapy (CRT) before surgery were randomized to standard of care (SOC) plus EUS-guided PTX injection or SOC alone. PTX was injected in 0.5 to 1.0 mL aliquots throughout the tumor. Planned CRT as SOC was intravenous 5-fluorouracil for the first 4 days (weeks 1 and 5), intravenous cisplatin on the first day of each 5-fluorouracil course, and radiotherapy over 5.5 weeks. Patients were evaluated weekly during CRT and re-evaluated at 12 weeks for surgical eligibility and CT for change in overall tumor volume. RESULTS: The analysis included 137 patients (97 males; mean age, 58 ± 9.1 years) randomized to PTX + SOC (n = 72) and SOC (n = 65) by using a modified intention-to-treat approach. Overall response by tumor volume between the PTX (12.5%) and the SOC group (20.0%; P = .24; odds ratio, 0.57; 95% confidence interval, 0.23-1.44) was similar. Pathologic complete response was higher in the SOC group (26.2% vs 12.5%; P = .046); however, 12-month survival (P = .412) and the overall frequency of 1 or more adverse events (P = .17) were similar between the 2 groups. CONCLUSIONS: SOC + PTX is safe but does not improve overall survival or overall tumor response at the primary tumor site for patients with local or locoregional cancer of the esophagus/gastroesophageal junction. (Clinical trial registration number: NCT00573131.).
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Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/terapia , Neoplasias Esofágicas/terapia , Adenocarcinoma/secundario , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Escamosas/secundario , Quimioradioterapia , Cisplatino/administración & dosificación , Endosonografía , Neoplasias Esofágicas/patología , Esofagectomía , Femenino , Fluorouracilo/administración & dosificación , Humanos , Inyecciones Intralesiones , Análisis de Intención de Tratar , Metástasis Linfática , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Radioterapia , Criterios de Evaluación de Respuesta en Tumores Sólidos , Tasa de Supervivencia , Carga TumoralRESUMEN
Clinical use of DC Bead™ loaded with doxorubicin (DEBDOX™) or irinotecan (DEBIRI™), for the treatment of primary and secondary tumours of the liver respectively, is showing great promise. Recently there has been a tendency to select smaller bead size ranges to treat tumours in an effort to allow more drug dose to be administered, improve tumoural penetration and resultant drug delivery and tumour coverage. Herein we describe the development and performance characterisation of a new DC Bead size range (DC BeadM1 (TM), 70-150 µm) capable of an increased bead delivery in the distal vasculature, corresponding to greater tumour coverage and drug dose delivered. Both unloaded and drug loaded DC BeadM1 were shown to have a greater density of distal volume of penetration although the ultimate distal level of penetration was the same as that of the 100-300 µm beads in an in vitro penetration model. Elution of doxorubicin was slower than irinotecan elution, but it was similar when comparing the same drug elution from 70 to 150 µm compared to 100-300 µm beads. Radiopaque versions of 70-150 and 100-300 µm beads were prepared in order to evaluate distribution ex vivo using µ-CT and doxorubicin distribution using epifluorescent microscopy. Liver distribution of the radiopaque versions of the beads was shown to be more distal and efficient at filling smaller vessels with the DC BeadM1 and correspondingly more beads were found per vessel histologically with a larger area of drug coverage with the smaller size range. This study indicates that the smaller (70-150 µm) beads should permit an increased dose of drug to be administered to both hypervascular and hypovascular tumours as compared to 100-300 µm beads.
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Antineoplásicos/administración & dosificación , Camptotecina/análogos & derivados , Catéteres , Doxorrubicina/administración & dosificación , Portadores de Fármacos , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Animales , Antineoplásicos/farmacocinética , Camptotecina/administración & dosificación , Camptotecina/farmacocinética , Doxorrubicina/farmacocinética , Irinotecán , Conejos , Microtomografía por Rayos XRESUMEN
OncoGel™ incorporates paclitaxel, a mitotic inhibitor, into ReGel™, a thermosensitive gel depot system to provide local delivery, enhance efficacy and limit systemic toxicity. In previous studies the alkylating agent temozolomide (TMZ) incorporated into a polymer, pCPP:SA, also for local delivery, and OncoGel were individually shown to increase efficacy in a rat glioma model. We investigated the effects of OncoGel with oral TMZ or locally delivered TMZ polymer, with and without radiotherapy (XRT) in rats with intracranial gliosarcoma. Eighty-nine animals were intracranially implanted with a 9L gliosarcoma tumor and divided into 12 groups that received various combinations of 4 treatment options; OncoGel 6.3 mg/ml (Day 0), 20 Gy XRT (Day 5), 50 % TMZ-pCPP:SA (Day 5), or oral TMZ (50 mg/kg, qd, Days 5-9). Animals were followed for survival for 120 days. Median survival for untreated controls, XRT alone or oral TMZ alone was 15, 19 and 28 days, respectively. OncoGel 6.3 or TMZ polymer alone extended median survival to 33 and 35 days, respectively (p = 0.0005; p < 0.0001, vs. untreated controls) with 50 % living greater than 120 days (LTS) in both groups. Oral TMZ/XRT extended median survival to 36 days (p = 0.0002), with no LTS. The group that received OncoGel and Oral TMZ did not reach median survival with 57 % LTS (p = 0.0002). All other combination groups [OncoGel/XRT], [TMZ polymer/XRT], [OncoGel/TMZ polymer], [OncoGel/TMZ polymer/XRT], and [OncoGel/oral TMZ/XRT] yielded greater than 50 % LTS (p < 0.0001 for each combination as compared to controls), therefore median survival was not reached. OncoGel/TMZ polymer and OncoGel/oral TMZ/XRT had 100 % LTS (p < 0.0001 and p = 0.0001 vs. oral TMZ/XRT, respectively). These results indicate that OncoGel given locally with oral or locally delivered TMZ and/or XRT significantly increased the number of LTS and improved median survival compared to oral TMZ and XRT given alone or in combination in a rodent intracranial gliosarcoma model.
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Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Dacarbazina/análogos & derivados , Glioma/tratamiento farmacológico , Glioma/radioterapia , Paclitaxel/uso terapéutico , Análisis de Varianza , Animales , Dacarbazina/uso terapéutico , Modelos Animales de Enfermedad , Sistemas de Liberación de Medicamentos/métodos , Quimioterapia Combinada , Femenino , Geles/uso terapéutico , Humanos , Trasplante de Neoplasias , Ratas , Ratas Endogámicas F344 , Análisis de Supervivencia , TemozolomidaRESUMEN
Synthetic arteriovenous (AV) hemodialysis grafts are plagued by hyperplasia resulting in occlusion and graft failure yet there are no clinically available preventative treatments. Here the delivery and degradation of a sirolimus-laden polymer gel were monitored in vivo by magnetic resonance imaging (MRI) and its efficacy for inhibiting hyperplasia was evaluated in a porcine model of AV graft stenosis. Synthetic grafts were placed between the carotid artery and ipsilateral jugular vein of swine. A biodegradable polymer gel loaded with sirolimus (2.5mg/mL) was immediately applied perivascularly to the venous anastomosis, and reapplied by ultrasound-guided injections at one, two and three weeks. Control grafts received neither sirolimus nor polymer. The lumen cross-sectional area at the graft-vein anastomosis was assessed in vivo by non-invasive MRI. The explanted tissues also underwent histological analysis. A specifically developed MRI pulse sequence provided a high contrast-to-noise ratio (CNR) between the polymer and surrounding tissue that allowed confirmation of gel location after injection. Polymer signal decreased up to 80% at three to four weeks after injection, slightly faster than its degradation kinetics in vitro. The MR image of the polymer was confirmed by visual assessment at necropsy. On histological assessment, the mean hyperplasia surface area of the treated graft was 52% lower than that of the control grafts (0.43mm(2) vs. 0.89mm(2); p<0.003), while the minimum cross-sectional lumen area, as measured on MRI, was doubled (5.3mm(2) vs 2.5mm(2); p<0.05). In conclusion, customized MRI allowed non-invasive monitoring of the location and degradation of drug delivery polymer gels in vivo. Perivascular application of sirolimus-laden polymer yielded a significant decrease in hyperplasia development and an increase in lumen area at the venous anastomosis of AV grafts.
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Antibióticos Antineoplásicos/administración & dosificación , Oclusión de Injerto Vascular/tratamiento farmacológico , Hiperplasia/tratamiento farmacológico , Polietilenglicoles/administración & dosificación , Poliglactina 910/administración & dosificación , Sirolimus/administración & dosificación , Animales , Antibióticos Antineoplásicos/sangre , Antibióticos Antineoplásicos/farmacocinética , Portadores de Fármacos/administración & dosificación , Geles , Oclusión de Injerto Vascular/metabolismo , Hiperplasia/metabolismo , Polietilenglicoles/farmacocinética , Poliglactina 910/farmacocinética , Diálisis Renal , Sirolimus/sangre , Sirolimus/farmacocinética , Sus scrofaRESUMEN
OBJECT: Treatment options for anaplastic or malignant intramedullary spinal cord tumors (IMSCTs) remain limited. Paclitaxel has potent cytotoxicity against experimental intracranial gliomas and could be beneficial in the treatment of IMSCTs, but poor CNS penetration and significant toxicity limit its use. Such limitations could be overcome with local intratumoral delivery. Paclitaxel has been previously incorporated into a biodegradable gel depot delivery system (OncoGel) and in this study the authors evaluated the safety of intramedullary injections of OncoGel in rats and its efficacy against an intramedullary rat gliosarcoma. METHODS: Safety of intramedullary OncoGel was tested in 12 Fischer-344 rats using OncoGel concentrations of 1.5 and 6.0 mg/ml (5 µl); median survival and functional motor scores (Basso-Beattie-Bresnahan [BBB] scale) were compared with those obtained with placebo (ReGel) and medium-only injections. Efficacy of OncoGel was tested in 61 Fischer-344 rats implanted with an intramedullary injection of 9L gliosarcoma containing 100,000 cells in 5 µl of medium, and randomized to receive OncoGel administered on the same day (in 32 rats) or 5 days after tumor implantation (in 29 rats) using either 1.5 mg/ml or 3.0 mg/ml doses of paclitaxel. Median survival and BBB scores were compared with those of ReGel-treated and tumor-only rats. Animals were killed after the onset of deficits for histopathological analysis. RESULTS: OncoGel was safe for intramedullary injection in rats in doses up to 5 µl of 3.0 mg/ml of paclitaxel; a dose of 5 µl of 6.0 mg/ml caused rapid deterioration in BBB scores. OncoGel at concentrations of 1.5 mg/ml and 3.0 mg/ml paclitaxel given on both Day 0 and Day 5 prolonged median survival and preserved BBB scores compared with controls. OncoGel 1.5 mg/ml produced 62.5% long-term survivors when delivered on Day 0. A comparison between the 1.5 mg/ml and the 3.0 mg/ml doses showed higher median survival with the 1.5 mg/ml dose on Day 0, and no differences in median survival or BBB scores after treatment on Day 5. CONCLUSIONS: OncoGel is safe for intramedullary injection in rats in doses up to 5 µl of 3.0 mg/ml, prolongs median survival, and increases functional motor scores in rats challenged with an intramedullary gliosarcoma at the doses tested. This study suggests that locally delivered chemotherapeutic agents could be of temporary benefit in the treatment of malignant IMSCTs under experimental settings.
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Antineoplásicos Fitogénicos/administración & dosificación , Gliosarcoma/tratamiento farmacológico , Paclitaxel/administración & dosificación , Paresia/tratamiento farmacológico , Neoplasias de la Médula Espinal/tratamiento farmacológico , Animales , Antineoplásicos Fitogénicos/uso terapéutico , Modelos Animales de Enfermedad , Sistemas de Liberación de Medicamentos , Femenino , Geles/administración & dosificación , Geles/uso terapéutico , Gliosarcoma/complicaciones , Paclitaxel/uso terapéutico , Paresia/etiología , Ratas , Ratas Endogámicas F344 , Neoplasias de la Médula Espinal/complicacionesRESUMEN
A monoclonal antibody (mAb) to P-glycoprotein (Pgp), UIC2, is used as a targeting moiety for N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer/drug [(meso chlorin e(6) mono(N-2-aminoethylamide) (Mce(6)) or doxorubicin (DOX)] conjugates to investigate their cytotoxicity towards the Pgp-expressing human ovarian carcinoma cell line A2780/AD. The binding, internalization, and subcellular trafficking of a fluorescein labeled UIC2 targeted HPMA copolymer are studied and show localization to the plasma membrane with limited internalization. The specificity of the UIC2-targeted HPMA copolymer/drug conjugates are confirmed using the sensitive cell line A2780 that does not express Pgp.
Asunto(s)
Resinas Acrílicas/química , Anticuerpos Monoclonales/química , Antineoplásicos/síntesis química , Membrana Celular/efectos de los fármacos , Doxorrubicina/química , Inmunoconjugados/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Resinas Acrílicas/metabolismo , Resinas Acrílicas/farmacología , Anticuerpos Monoclonales/farmacología , Antineoplásicos/farmacología , Carcinoma/tratamiento farmacológico , Carcinoma/patología , Línea Celular Tumoral/efectos de los fármacos , Membrana Celular/metabolismo , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/farmacología , Portadores de Fármacos , Resistencia a Antineoplásicos , Endocitosis/efectos de los fármacos , Femenino , Fluoresceína , Humanos , Inmunoconjugados/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patologíaRESUMEN
OBJECT: Paclitaxel, a cellular proliferation inhibitor/radiation sensitizer, while effective against gliomas in vitro, has poor CNS penetration and dose-limiting toxicities when administered systemically. OncoGel (paclitaxel in Re-Gel) provides controlled local paclitaxel release when placed into the CNS. The authors evaluated the safety and efficacy of OncoGel in rats with intracranial 9L gliosarcoma. METHODS: Safety studies included intracranial delivery of increasing volumes of ReGel and OncoGel containing 1.5 (OncoGel 1.5) or 6.3 (OncoGel 6.3) mg/ml paclitaxel. An in vivo radiolabeled biodistribution study was performed in 18 Fischer-344 rats to determine intracerebral distribution. Efficacy studies compared overall survival for controls, ReGel only, radiation therapy only, OncoGel 6.3, or OncoGel 6.3 in combination with radiation therapy. ReGel and OncoGel 6.3 were delivered either simultaneously with tumor implantation (Day 0) or 5 days later (Day 5). Radiation therapy was given on Day 5. RESULTS: Control and ReGel animals died of tumor within 17 days. Survival significantly increased in the Onco-Gel 6.3 group on Day 0 (median 31 days; p = 0.0001), in the OncoGel 6.3 group on Day 5 (median 17 days; p = 0.02), and in the radiation therapy-only group (median 26 days; p = 0.0001) compared with controls. Animals receiving both OncoGel and radiation therapy had the longest median survival: 83 days in the group with radiation therapy combined with OncoGel 6.3 on Day 0, and 32 days in the group combined with OncoGel 6.3 on Day 5 (p = 0.0001 vs controls). After 120 days, 37.5% of the animals in the OncoGel Day 0 group, 37.5% of animals in the OncoGel 6.3 Day 0 in combination with radiation therapy group, and 12.5% of the animals in the OncoGel 6.3 on Day 5 in combination with radiation therapy group were alive. In the biodistribution study, measurable radioactivity was observed throughout the ipsilateral hemisphere up to 3 weeks after the OncoGel injection, with the most radioactivity detected 3 hours after injection. The highest dose of radioactivity observed in the contralateral hemisphere was at the Day 3 time point. CONCLUSIONS: OncoGel containing 6.3 mg/ml of paclitaxel is safe for intracranial injection in rats and effective when administered on Day 0. When combined with radiation therapy, the combination was more effective than either therapy alone and should be studied clinically for the treatment of malignant glioma.
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Antineoplásicos Fitogénicos/farmacocinética , Neoplasias Encefálicas/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/métodos , Gliosarcoma/tratamiento farmacológico , Paclitaxel/farmacocinética , Animales , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Femenino , Geles , Gliosarcoma/mortalidad , Gliosarcoma/patología , Inyecciones Intralesiones , Estimación de Kaplan-Meier , Trasplante de Neoplasias , Ratas , Ratas Endogámicas F344 , Distribución TisularRESUMEN
Cancer treatment regimens often include multiple anticancer agents targeting different cellular mechanisms in delicate balance with associated toxicity. Drug delivery systems offer a unique tool in the treatment of cancer, and applications in the local treatment of cancer have demonstrated utility in providing sustained high local concentrations at the tumor site while minimizing systemic drug levels. Treatment options for local cancer therapy are focused on indications where targeted activity may result in improved patient outcomes such as increased local control and decreased metastatic potential. Targeted therapies may also enhance response to combination anticancer regimens. OncoGel, a controlled-release depot formulation of paclitaxel in ReGel, has been evaluated in numerous nonclinical studies. Results from these studies demonstrated OncoGel's ability to physically target paclitaxel to the tumor site with very little reaching the circulation, resulting in an acceptable safety profile with dose-limiting toxicities being local in nature. In addition, OncoGel demonstrated efficacy as a stand-alone treatment and synergistic activity in combination therapies. Clinical studies in superficially-palpable tumors and esophageal carcinoma confirmed local paclitaxel release from OncoGel in patients. OncoGel's ability to improve current treatment options for esophageal and brain cancers is being further evaluated.
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Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias/tratamiento farmacológico , Paclitaxel/administración & dosificación , Polietilenglicoles , Poliglactina 910 , Antineoplásicos Fitogénicos/farmacocinética , Antineoplásicos Fitogénicos/uso terapéutico , Terapia Combinada , Preparaciones de Acción Retardada , Relación Dosis-Respuesta a Droga , Portadores de Fármacos , Humanos , Neoplasias/terapia , Paclitaxel/farmacocinética , Paclitaxel/uso terapéuticoRESUMEN
OncoGel, a novel injectable formulation of paclitaxel in a biocompatible biodegradable gel (ReGel), provides controlled release of paclitaxel at the injection site, resulting in high intralesional paclitaxel concentrations and continuous radiosensitization without attendant systemic toxicities. This dose-escalation study evaluated the toxicity, pharmacokinetics, and preliminary antitumor activity of OncoGel injected intralesionally in patients with inoperable esophageal cancer who were candidates for palliative external-beam radiotherapy (RT). Eleven patients with inoperable advanced esophageal cancer received a single administration of OncoGel into the primary tumor using conventional endoscopic techniques. Three cohorts received approximately one-third of the tumor volume with increasing paclitaxel concentrations to achieve 0.48, 1.0, and 2.0 mg paclitaxel/cm tumor volume. Subsequent to injection, RT was initiated (50.4 Gy in 1.8 Gy fractions). Pharmacokinetic sampling was performed. All patients completed the study. No dose-limiting toxicities were reported. Dysphagia improved and tumor size decreased in most patients. Biopsies were negative for carcinoma in 4 of 11 patients. Peak paclitaxel plasma concentrations were low (0.53-2.73 ng/ml) and directly related to the absolute amount of paclitaxel administered. Paclitaxel was detectable in plasma for 24 h in all patients and for 3 weeks in six patients. OncoGel given as an adjunct to RT was well tolerated in patients with inoperable esophageal cancer and provided prolonged paclitaxel release with minimal systemic exposure. OncoGel plus RT seemed to reduce tumor burden as evidenced by dysphagia improvement, tumor size reduction, and negative esophageal biopsies. The addition of OncoGel to combined modality therapy merits continued clinical development.
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Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/radioterapia , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Anciano , Terapia Combinada , Trastornos de Deglución/tratamiento farmacológico , Trastornos de Deglución/etiología , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/uso terapéutico , Neoplasias Esofágicas/complicaciones , Neoplasias Esofágicas/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Paclitaxel/efectos adversos , Paclitaxel/farmacocinética , Resultado del TratamientoRESUMEN
OncoGel is a novel depot formulation of paclitaxel designed for intralesional injection with a sustained paclitaxel delivery over approximately 6 weeks from a single administration. This phase 1 study was designed to characterize the toxicity, pharmacokinetics and preliminary antitumor activity associated with OncoGel administered directly into solid tumors. OncoGel was injected into 18 superficially accessible advanced solid cancerous lesions among 16 adult patients for whom no curative therapy was available. Four dose cohorts were evaluated, ranging from 0.06 to 2.0 mg paclitaxel/cm3 tumor volume. OncoGel injections were generally well tolerated. There was one report of grade 3 injection site pain for a patient in the 0.25 mg paclitaxel/cm3 tumor volume dose cohort. Other adverse events considered related to the study drug included mild to moderate local responses to the injection itself. Systemic levels of paclitaxel were detectable only in 3.3% of the samples analyzed (range: 0.53-0.71 ng/ml). For the 14 patients evaluable for disease progression, stable disease was noted among six patients and progressive disease among eight patients. Although the maximum tolerated dose was not identified, the planned maximum dose was administered in the study. OncoGel delivered intralesionally at doses up to 2.0 mg paclitaxel/cm3 tumor volume was well tolerated and paclitaxel remained localized at the injection site, confirming design principles to minimize systemic exposure. Therefore, localized paclitaxel administration using OncoGel merits continued clinical development.
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Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Fitogénicos/farmacocinética , Preparaciones de Acción Retardada , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Inyecciones , Masculino , Persona de Mediana Edad , Paclitaxel/farmacocinéticaRESUMEN
BACKGROUND: OncoGel (ReGel/paclitaxel) is an intralesional injectable formulation of the chemotherapeutic drug, paclitaxel, for local tumor management. OBJECTIVE: The aim of this study was to determine if a minimally invasive EUS-guided injection of paclitaxel, bound to a thermosensitive gel carrier, would lead to therapeutic tissue concentrations of the chemotherapeutic agent in the porcine pancreas. DESIGN: Eight Yorkshire breed pigs were sedated by general anesthesia and OncoGel was injected, under EUS-guidance, with a 22-gauge needle into the tail of the pancreas. MAIN OUTCOME MEASUREMENTS: During the 7-day (n = 4) or 14-day (n = 4) observational period, the animals were monitored by serum levels of amylase and lipase, and by a CT on day 4. The outcome was determined by gross and microscopic evidence of inflammation of the pancreas, clinical tolerance, and quantitation of tissue paclitaxel concentrations. RESULTS: Eight pigs underwent injection of 1, 2, 3, or 4 mL OncoGel (6 mg paclitaxel per 1 mL OncoGel) (n = 2 per group). An intrapancreatic hyperechoic focus, with an average diameter of 2.1 +/- 0.8 cm, was visible by EUS, and a hypodense area in the tail of the pancreas was visible by contrast CT. Clinically, the animals appeared to tolerate the procedure without sequelae. Blood levels of amylase and lipase were normal. At euthanasia, a depot of OncoGel, with an average diameter of 14.7 +/- 5.0 mm), was located both grossly and histologically in the pancreatic tail. After 14 days, clinically significant tissue concentrations of paclitaxel were detected at a distance of 30 to 50 mm from the depot in the animals that underwent an injection of 3 and 4 mL of the agent (n = 2). CONCLUSIONS: The EUS-guided injection of OncoGel into the pancreas of the pig provided high and sustained localized concentrations of paclitaxel. This technique is a potential minimally invasive local treatment option for unresectable pancreatic tumors.
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Antineoplásicos Fitogénicos/administración & dosificación , Endosonografía/métodos , Paclitaxel/administración & dosificación , Páncreas , Grabación en Video , Animales , Antineoplásicos Fitogénicos/farmacocinética , Antineoplásicos Fitogénicos/uso terapéutico , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Endosonografía/veterinaria , Femenino , Inyecciones Intralesiones , Masculino , Paclitaxel/farmacocinética , Paclitaxel/uso terapéutico , Páncreas/diagnóstico por imagen , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Porcinos , Tomografía Computarizada por Rayos XRESUMEN
ReGel is an aqueous, filter sterilizable ABA tri-block polymer consisting of poly-(lactide-co-glycolide) and polyethylene glycol. We tested the suitability of this polymer to provide sustained interleukin-2 (IL-2) delivery for cancer immunotherapy. ReGel/IL-2 is liquid at or below room temperature, and is easily injectable through narrow gauge needles, but undergoes a reversible thermal transition into a bioerodible depot at body temperature. We demonstrated that ReGel/IL-2 releases IL-2 over 72 to 96 hours in vitro, without loss of bioactivity. Pharmacokinetic studies after peritumoral injection of 0.1 mL ReGel/IL-2 in mice demonstrated an early burst of IL-2 release, followed by more sustained release kinetics over 96 hours (T(1/2)beta 48 h). Less than 1.5% of the injected dose was detectable in blood or kidneys during the first 48 hours. A single peritumoral dose of ReGel/IL-2 [1 to 4 million international units (MIU) ReGel/IL-2, split into 4 quadrant injections] was administered to mice bearing subcutaneous RD-995 spindle cell carcinoma. Only the highest dose of ReGel/IL-2 tested (4.0 MIU) resulted in significant hypotension on day 3 after injection. Weekly treatment of Meth A fibrosarcoma and RENCA renal carcinoma with ReGel/IL-2 (2 MIU/dose) induced a significant reduction in tumor growth and improved survival. Reduction in tumor growth at implants remote from treated lesions was also observed, suggesting systemic activation of antitumor immunity. These findings establish that peritumoral injection of ReGel/IL-2 is an effective delivery system for cancer immunotherapy, while decreasing IL-2 toxicity. This polymer delivery system is likely to be broadly applicable for sustained delivery of other cytokines and peptides.