RESUMO
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.
Assuntos
Carcinoma Hepatocelular , Embolização Terapêutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/radioterapia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/tratamento farmacológico , Estudos Retrospectivos , Reprodutibilidade dos Testes , Agregado de Albumina Marcado com Tecnécio Tc 99m , Tomografia Computadorizada de Emissão de Fóton Único , Radioisótopos de Ítrio/uso terapêutico , Microesferas , Embolização Terapêutica/efeitos adversosRESUMO
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.
Assuntos
Carcinoma Hepatocelular , Embolização Terapêutica , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/radioterapia , Embolização Terapêutica/efeitos adversos , Humanos , Hiperbilirrubinemia/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/radioterapia , Microesferas , Estudos Retrospectivos , Resultado do Tratamento , Radioisótopos de Ítrio/uso terapêutico , alfa-FetoproteínasRESUMO
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.
Assuntos
Antineoplásicos/administração & dosagem , Camptotecina/análogos & derivados , Catéteres , Doxorrubicina/administração & dosagem , Portadores de Fármacos , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Animais , Antineoplásicos/farmacocinética , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Doxorrubicina/farmacocinética , Irinotecano , Coelhos , Microtomografia por Raio-XRESUMO
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.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Dacarbazina/análogos & derivados , Glioma/tratamento farmacológico , Glioma/radioterapia , Paclitaxel/uso terapêutico , Análise de Variância , Animais , Dacarbazina/uso terapêutico , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/métodos , Quimioterapia Combinada , Feminino , Géis/uso terapêutico , Humanos , Transplante de Neoplasias , Ratos , Ratos Endogâmicos F344 , Análise de Sobrevida , TemozolomidaRESUMO
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.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Oclusão de Enxerto Vascular/tratamento farmacológico , Hiperplasia/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Poliglactina 910/administração & dosagem , Sirolimo/administração & dosagem , Animais , Antibióticos Antineoplásicos/sangue , Antibióticos Antineoplásicos/farmacocinética , Portadores de Fármacos/administração & dosagem , Géis , Oclusão de Enxerto Vascular/metabolismo , Hiperplasia/metabolismo , Polietilenoglicóis/farmacocinética , Poliglactina 910/farmacocinética , Diálise Renal , Sirolimo/sangue , Sirolimo/farmacocinética , Sus scrofaRESUMO
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.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Gliossarcoma/tratamento farmacológico , Paclitaxel/administração & dosagem , Paresia/tratamento farmacológico , Neoplasias da Medula Espinal/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Feminino , Géis/administração & dosagem , Géis/uso terapêutico , Gliossarcoma/complicações , Paclitaxel/uso terapêutico , Paresia/etiologia , Ratos , Ratos Endogâmicos F344 , Neoplasias da Medula Espinal/complicaçõesRESUMO
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.
Assuntos
Resinas Acrílicas/química , Anticorpos Monoclonais/química , Antineoplásicos/síntese química , Membrana Celular/efeitos dos fármacos , Doxorrubicina/química , Imunoconjugados/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Resinas Acrílicas/metabolismo , Resinas Acrílicas/farmacologia , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Carcinoma/tratamento farmacológico , Carcinoma/patologia , Linhagem Celular Tumoral/efeitos dos fármacos , Membrana Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Portadores de Fármacos , Resistencia a Medicamentos Antineoplásicos , Endocitose/efeitos dos fármacos , Feminino , Fluoresceína , Humanos , Imunoconjugados/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologiaRESUMO
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.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Neoplasias Encefálicas/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Gliossarcoma/tratamento farmacológico , Paclitaxel/farmacocinética , Animais , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Feminino , Géis , Gliossarcoma/mortalidade , Gliossarcoma/patologia , Injeções Intralesionais , Estimativa de Kaplan-Meier , Transplante de Neoplasias , Ratos , Ratos Endogâmicos F344 , Distribuição TecidualRESUMO
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.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Polietilenoglicóis , Poliglactina 910 , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/uso terapêutico , Terapia Combinada , Preparações de Ação Retardada , Relação Dose-Resposta a Droga , Portadores de Fármacos , Humanos , Neoplasias/terapia , Paclitaxel/farmacocinética , Paclitaxel/uso terapêuticoRESUMO
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.
Assuntos
Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/radioterapia , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Idoso , Terapia Combinada , Transtornos de Deglutição/tratamento farmacológico , Transtornos de Deglutição/etiologia , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/uso terapêutico , Neoplasias Esofágicas/complicações , Neoplasias Esofágicas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinética , Resultado do TratamentoRESUMO
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.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Fitogênicos/farmacocinética , Preparações de Ação Retardada , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Paclitaxel/farmacocinéticaRESUMO
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.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Endossonografia/métodos , Paclitaxel/administração & dosagem , Pâncreas , Gravação em Vídeo , Animais , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/uso terapêutico , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Endossonografia/veterinária , Feminino , Injeções Intralesionais , Masculino , Paclitaxel/farmacocinética , Paclitaxel/uso terapêutico , Pâncreas/diagnóstico por imagem , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Suínos , Tomografia Computadorizada por Raios XRESUMO
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.