RESUMEN
Bevacizumab, temozolomide (TMZ), and radiotherapy are three therapeutic methods, but the combination of them as a new approach for the treatment of newly diagnosed high-grade gliomas (HGGs) is still under investigation. Therefore, this study aims to evaluate the safety, efficacy, and clinical utility of this treatment approach for patients with glioblastoma (GBM). PubMed/Medline, Scopus, Embase, and Web of Science were systematically reviewed from inception to 24 August 2023. Relevant studies evaluating the therapeutic effect of adding Bevacizumab to TMZ-based chemotherapy and radiation therapy were enrolled. All statistical analysis was performed using the "meta" package of R. A total of 21 studies were included in this study. Our meta-analysis found that adding bevacizumab to standard therapy improved progression-free survival (PFS) in patients with newly diagnosed GBM. The pooled 6-month PFS rate was significantly higher with bevacizumab (79% vs. 56%, odds ratio 3.17). Overall survival (OS) showed modest improvements, with 2-year OS rates of 39% vs. 20% favoring bevacizumab. Radiological response rates varied, with a pooled overall response rate of 44% for bevacizumab-treated patients. The complete response rate was 16%, partial response 32%, and progressive disease 25%. Adverse events occurred in 62% of bevacizumab-treated patients. Common complications included fatigue, thrombocytopenia, and thromboembolic events. When added to standard therapy, bevacizumab demonstrates modest improvements in PFS and OS for newly diagnosedGBM. While it shows promise in short-term outcomes and radiological responses, long-term survival benefits remain limited. The risk of adverse events, particularly CNS hemorrhage, necessitates careful patient selection. These findings suggest that bevacizumab may have a role in treating high-grade gliomas, but its use should be individualized based on patient characteristics and risk-benefit assessment.
Asunto(s)
Bevacizumab , Neoplasias Encefálicas , Glioblastoma , Temozolomida , Bevacizumab/uso terapéutico , Bevacizumab/administración & dosificación , Humanos , Temozolomida/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/terapia , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/terapia , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/administración & dosificación , Supervivencia sin Progresión , Quimioradioterapia/métodosRESUMEN
Rising cure rates in pediatric cancer patients warrants an increased attention toward the long-term consequences of the diagnosis and treatment in survivors. Chemotherapeutic agents can be gonadotoxic, rendering them at risk for infertility post-survival. While semen cryopreservation is an option that can be provided for most (post)pubertal boys before treatment, this is unfortunately not an option prepubertal in age, simply due to the lack of spermatogenesis. Over the last couple of years, studies have thus focused on better understanding the testis niche in response to various chemotherapeutic agents that are commonly administered and their direct and indirect impact on the germ cell populations. These are generally compounds that have a high risk of infertility and have been classified into risk categories in curated fertility guidelines. However, with it comes the lack of evidence and the challenge of using informative models and conditions most reflective of the physiological scenario, in short, the appropriate study designs for clinically relevant outcomes. Besides, the exact mechanism(s) of action for many of these "risk" compounds as well as other agents is unclear. Understanding their behavior and effect on the testis niche will pave the way for incorporating new strategies to ultimately combat infertility. Of the various drug classes, alkylating agents pose the highest risk of gonadotoxicity as per previously established studies as well as risk stratification guidelines. Therefore, this review will summarize the findings in the field of male fertility concerning gonadotoxicity of akylating agents as a result of chemotherapy exposure.
Asunto(s)
Antineoplásicos Alquilantes , Testículo , Humanos , Masculino , Testículo/efectos de los fármacos , Niño , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/administración & dosificación , Infertilidad Masculina/inducido químicamente , Infertilidad Masculina/etiología , Infertilidad Masculina/diagnóstico , Animales , Espermatogénesis/efectos de los fármacos , Espermatogénesis/efectos de la radiación , Neoplasias/tratamiento farmacológico , Pubertad/efectos de los fármacos , Pubertad/fisiología , Alquilantes/efectos adversos , Alquilantes/administración & dosificaciónRESUMEN
A male patient started PCV chemotherapy (a combination of procarbazine, lomustine and vincristine) for a recurrent oligodendroglioma grade 2. Unfortunately, our patient took an unintended overdose of lomustine during the first PCV course: instead of 160 mg absolute dose of lomustine on day 1 only, he consumed 160 mg absolute dose of lomustine for seven consecutive days to a total dose of 1120 mg. Pancytopenia became evident after 24 days, and several months of severe myelosuppression, infections, reduced general condition, and nutrition difficulties followed. Fortunately, our patient with time recovered his bone marrow function. However, the patient's quality of life was reduced for a long time and several lessons were learnt: oral and written information on chemotherapy is essential, but not always sufficient to ensure the correct dosing of patient-administered chemotherapy. Oral chemotherapeutics should be delivered as a single-dose supply or be administered by experienced health personnel.
Asunto(s)
Neoplasias Encefálicas , Sobredosis de Droga , Lomustina , Oligodendroglioma , Humanos , Lomustina/administración & dosificación , Masculino , Neoplasias Encefálicas/tratamiento farmacológico , Oligodendroglioma/tratamiento farmacológico , Pancitopenia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Glioma/tratamiento farmacológico , Calidad de Vida , Persona de Mediana EdadRESUMEN
Cyclophosphamide and ifosfamide are major alkylating agents but their therapeutics uses are limiting by the toxicity due to several toxicities. Indeed conventional chemotherapies are generally used with the maximum tolerated dose. In contrast, metronomic schedule aims to get a minimum dose for efficacy with a good safety. Depending on the dose, their mechanisms of action are different and offer a dual activity: at high dose, cyclophosphamide is mainly used in graft conditioning for its immunosuppressive properties, while at metronomic dose it is used as an immunoactive agent. Currently, at metronomic dose, cyclophosphamide is studied in clinic against various types of cancer, alone or in combination with others anticancer drugs (anti-angiogenic, immune-modulating agents, immune checkpoints blockers, vaccines, radiotherapy, others conventional anticancer agents), as a nth-line or first-line treatment. More than three quarters of clinical studies show promising results, mostly in breast, ovarian and prostate cancers. Taking advantage of the immune system, use dual antitumor action's chemotherapy is clearly a therapeutic strategy that deserves to be confirmed in order to improve the efficacy/toxicity balance of anticancer treatments, and to use CPM or analogues as a standard of care.
Asunto(s)
Ciclofosfamida , Neoplasias , Humanos , Ciclofosfamida/farmacología , Ciclofosfamida/administración & dosificación , Neoplasias/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/administración & dosificación , Administración Metronómica , Ifosfamida/administración & dosificación , Relación Dosis-Respuesta a DrogaRESUMEN
Radiotherapy combined with temozolomide (TMZ+RT) is the primary treatment for high-grade glioma. TMZ is classified as a moderate emetic risk agent and, thus, supportive care for nausea and vomiting is important. In Nagoya University Hospital, all patients are treated with a 5-hydroxy-tryptamine 3 receptor antagonist (5-HT3RA) for the first 3 days. The daily administration of 5-HT3RA is resumed after the 4th day based on the condition of patients during TMZ+RT. Therefore, the present study investigated risk factors for nausea and vomiting in patients requiring the daily administration of 5-HT3RA. Patients with high-grade glioma who received TMZ+RT between January 2014 and December 2019 at our hospital were included. Patients were divided into two groups: a control group (patients who did not resume 5-HT3RA) and resuming 5-HT3RA group (patients who resumed 5-HT3RA after the 4th day), and both groups were compared to identify risk factors for nausea and vomiting during TMZ+RT. There were 78 patients in the control group (68%) and 36 in the resuming 5-HT3RA group (32%). A multivariate analysis of patient backgrounds in the two groups identified age <18 years, PS 2 or more, and occipital lobe tumors as risk factors for nausea and vomiting. Nausea and vomiting were attenuated in 30 patients (83%) in the resuming 5-HT3RA group following the resumption of 5-HT3RA. The results obtained highlight the importance of extracting patients with these risk factors before the initiation of therapy and the early resumption or daily administration of 5-HT3RA according to the condition of each patient.
Asunto(s)
Glioma , Náusea , Antagonistas del Receptor de Serotonina 5-HT3 , Temozolomida , Vómitos , Humanos , Temozolomida/uso terapéutico , Temozolomida/administración & dosificación , Temozolomida/efectos adversos , Masculino , Antagonistas del Receptor de Serotonina 5-HT3/uso terapéutico , Antagonistas del Receptor de Serotonina 5-HT3/administración & dosificación , Femenino , Vómitos/inducido químicamente , Vómitos/tratamiento farmacológico , Persona de Mediana Edad , Glioma/tratamiento farmacológico , Glioma/radioterapia , Factores de Riesgo , Anciano , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Adulto , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/administración & dosificación , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodosRESUMEN
Treating metastatic malignancies to the central nervous system (CNS) is challenging because many drugs cannot cross the blood-brain-barrier (BBB). Direct intrathecal (IT) drug administration into the cerebrospinal fluid (CSF) is a strategy to overcome this problem. Thiotepa has effective CNS penetration but its popularity has waned over the last two decades due to concerns about its efficacy and potential systemic toxicity. This review evaluates the available evidence for the use of IT thiotepa in hematologic malignancies and non-CNS solid tumors with leptomeningeal disease metastases (LMD). Our search shows that IT thiotepa is a reasonable alternative in hematologic malignancies and LMD due to solid organ malignancies. This suggests a potential role of IT thiotepa in second-or third-line treatment or a substitute role in cases of drug-shortages and adverse effects with other agents. Future research should focus on rigorous comparative trials to establish its definitive role in the evolving landscape of CNS-directed chemotherapy.
Asunto(s)
Neoplasias del Sistema Nervioso Central , Inyecciones Espinales , Tiotepa , Humanos , Tiotepa/administración & dosificación , Tiotepa/efectos adversos , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/secundario , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Meníngeas/tratamiento farmacológico , Neoplasias Meníngeas/secundarioRESUMEN
In the era of single and combination maintenance therapies as well as platinum and Poly (ADP-ribose) polymerase inhibitors (PARPi) resistance, the choice of subsequent treatments following first-line platinum-based chemotherapy in recurrent ovarian cancer (ROC) patients has become increasingly complex. Within the ovarian cancer treatment algorithm, particularly in the emerging context of PARPi resistance, the role of trabectedin, in combination with pegylated liposomal doxorubicin (PLD) still preserves its significance. This paper offers valuable insights into the multifaceted role and mechanism of action of trabectedin in ROC. The main results of clinical trials and studies involving trabectedin/PLD, along with hints of Breast Cancer genes (BRCA)-mutated and BRCAness phenotype cases, are critically discussed. Moreover, this review provides and contextualizes potential scenarios of administering trabectedin in combination with PLD in ROC, according to established guidelines and beyond.
Asunto(s)
Neoplasias Ováricas , Trabectedina , Trabectedina/uso terapéutico , Trabectedina/farmacología , Trabectedina/administración & dosificación , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Femenino , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/administración & dosificación , Tetrahidroisoquinolinas/farmacología , Tetrahidroisoquinolinas/uso terapéutico , Tetrahidroisoquinolinas/administración & dosificación , Dioxoles/farmacología , Dioxoles/uso terapéutico , Dioxoles/administración & dosificación , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Polietilenglicoles/administración & dosificación , Polietilenglicoles/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: The prognosis of patients with Relapsed/Refractory Osteosarcoma (R/R OS) remains dismal without an agreement on systemic therapy. The use of High-Dose Ifosfamide (14 g/sqm) with an external pump in outpatient setting (14-IFO) in R/R OS patients is limited. This study represents the first retrospective cohort analysis focused on evaluating the activity and toxicity of 14-IFO in this setting. PATIENTS AND METHODS: The study investigated 14-IFO activity, in terms of tumour response according to RECIST 1.1 criteria, as well as survival rates and toxicity, according to CTCAE v.5. RESULTS: The trial enrolled 26 patients with R/R OS. The Overall Response Rate (ORR) and Disease Control Rate (DCR) obtained was 23% and 57.5%, respectively. Patients with relapsed OS showed a higher ORR (45%) and DCR (82%) compared to refractory patients, irrespective of the number of prior treatment lines received. The achievement of disease control with 14-IFO administration enabled 27% of patients to undergo new local treatment. Four-month Progression-Free Survival (PFS) was 54% for all patients and 82% for the relapsed OS sub-group. Median Overall Survival (OSurv) was 13.7 months, with 1-year OSurv of 51% for all patients and 71% for relapsed patients. Age over 18 years and the presence of refractory disease were identified as negative prognostic factors for this patient cohort. A total of 101 cycles were evaluated for toxic assessment, demonstrating a tolerable profile without grade 3-4 non-haematological toxicities. CONCLUSIONS: 14-IFO should be considered a viable treatment option for R/R OS, particularly due to its well tolerated toxicity profile and the potential for home-administration, which can improve patient quality of life without compromising efficacy.
Asunto(s)
Neoplasias Óseas , Ifosfamida , Recurrencia Local de Neoplasia , Osteosarcoma , Humanos , Ifosfamida/administración & dosificación , Ifosfamida/efectos adversos , Ifosfamida/uso terapéutico , Masculino , Femenino , Estudios Retrospectivos , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/mortalidad , Osteosarcoma/patología , Adulto , Adolescente , Adulto Joven , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Persona de Mediana Edad , Niño , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/efectos adversos , Clasificación del Tumor , Resultado del TratamientoRESUMEN
PURPOSE: We report our experience disrupting the blood-brain barrier (BBB) to improve drug delivery in glioblastoma patients receiving temozolomide chemotherapy. The goals of this retrospective analysis were to compare MRI-based measures of BBB disruption and vascular damage to the exposure levels, acoustic emissions data, and acoustic simulations. We also simulated the cavitation detectors. METHODS: Monthly BBB disruption (BBBD) was performed using a 220 kHz hemispherical phased array focused ultrasound system (Exablate Neuro, InSightec) and Definity microbubbles (Lantheus) over 38 sessions in nine patients. Exposure levels were actively controlled via the cavitation dose obtained by monitoring subharmonic acoustic emissions. The acoustic field and sensitivity profile of the cavitation detection system were simulated. Exposure levels and cavitation metrics were compared to the level of BBBD evident in contrast-enhanced MRI and to hypointense regions in T2*-weighted MRI. RESULTS: Our treatment strategy evolved from using a relatively high cavitation dose goal to a lower goal and longer sonication duration and ultimately resulted in BBBD across the treatment volume with minimal petechiae. Subsonication-level feedback control of the exposure using acoustic emissions also improved consistency. Simulations of the acoustic field suggest that reflections and standing waves appear when the focus is placed near the skull, but their effects can be mitigated with aberration correction. Simulating the cavitation detectors suggest variations in the sensitivity profile across the treatment volume and between patients. A correlation was observed with the cavitation dose, BBBD and petechial hemorrhage in 8/9 patients, but substantial variability was evident. Analysis of the cavitation spectra found that most bursts did not contain wideband emissions, a signature of inertial cavitation, but biggest contribution to the cavitation dose - the metric used to control the procedure - came from bursts with wideband emissions. CONCLUSION: Using a low subharmonic cavitation dose with a longer duration resulted in BBBD with minimal petechiae. The correlation between cavitation dose and outcomes demonstrates the benefits of feedback control based on acoustic emissions, although more work is needed to reduce variability. Acoustic simulations could improve focusing near the skull and inform our analysis of acoustic emissions. Monitoring additional frequency bands and improving the sensitivity of the cavitation detection could provide signatures of microbubble activity associated with BBB disruption that were undetected here and could improve our ability to achieve BBB disruption without vascular damage.
Asunto(s)
Barrera Hematoencefálica , Neoplasias Encefálicas , Glioblastoma , Imagen por Resonancia Magnética , Microburbujas , Humanos , Barrera Hematoencefálica/metabolismo , Glioblastoma/diagnóstico por imagen , Glioblastoma/tratamiento farmacológico , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/tratamiento farmacológico , Imagen por Resonancia Magnética/métodos , Estudios Retrospectivos , Persona de Mediana Edad , Temozolomida/administración & dosificación , Temozolomida/uso terapéutico , Masculino , Antineoplásicos Alquilantes/administración & dosificación , Femenino , Sistemas de Liberación de Medicamentos , Anciano , Acústica , Adulto , Simulación por ComputadorRESUMEN
BACKGROUND: The aims of this study are to report our experience with treosulfan-based conditioning regimens for patients with non-malignant hematologic conditions, correlating clinical outcomes at different time points post-transplant with treosulfan exposure (AUC). METHODS: This study was a single-center observational study investigating overall survival (OS), disease-free survival (DFS), and event-free survival (EFS) end-points post-transplant. The consequences of treosulfan AUC with respect to toxicity, correction of underlying disease, and long-term chimerism were also explored using pharmacokinetic analysis. RESULTS: Forty-six patients received 49 transplants with treosulfan and fludarabine-based conditioning between 2005 and 2023. Twenty-four patients also received thiotepa. Donor chimerism was assessed on either whole blood or sorted cell lines at different time points post-transplant. Thirty-nine patients received treosulfan pharmacokinetic assessment to evaluate cumulative AUC, with five infants receiving real-time assessment to facilitate daily dose adjustment. OS, DFS, and EFS were 87%, 81%, and 69%, respectively. Median follow-up was 32.1 months (range 0.82-160 months) following transplant. Lower EFS was associated with patient age (<1 year; p = .057) and lower cumulative treosulfan dose (<42 g/m2; p = .003). Stable donor chimerism in B-cell, NK-cell, and granulocyte lineages at 1-year post-transplant were more prevalent in patients receiving thiotepa conditioning. Two infants required daily dose adjustment to treosulfan to avoid high AUC. CONCLUSIONS: Excellent clinical outcomes and stable chimerism were observed in this patient series. The addition of thiotepa conferred no significant toxicity and trended toward sustained ongoing donor engraftment. Correlating treosulfan AUC with long-term patient outcomes is required.
Asunto(s)
Busulfano , Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante , Humanos , Busulfano/análogos & derivados , Busulfano/uso terapéutico , Busulfano/farmacocinética , Busulfano/administración & dosificación , Acondicionamiento Pretrasplante/métodos , Masculino , Trasplante de Células Madre Hematopoyéticas/métodos , Femenino , Lactante , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Resultado del Tratamiento , Estudios Retrospectivos , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Vidarabina/administración & dosificación , Tiotepa/uso terapéutico , Tiotepa/administración & dosificación , Tiotepa/farmacocinética , Supervivencia sin Enfermedad , Estudios de Seguimiento , Enfermedades Hematológicas/terapia , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/farmacocinética , Antineoplásicos Alquilantes/administración & dosificaciónRESUMEN
BACKGROUND: Uveal melanoma (UM) has a poor prognosis once liver metastases occur. The melphalan/Hepatic Delivery System (melphalan/HDS) is a drug/device combination used for liver-directed treatment of metastatic UM (mUM) patients. The purpose of the FOCUS study was to assess the efficacy and safety of melphalan/HDS in patients with unresectable mUM. METHODS: Eligible patients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of six cycles. The primary end point was the objective response rate (ORR). The secondary end points included duration of response (DOR), overall survival (OS), and progression-free survival (PFS). RESULTS: The study enrolled 102 patients with mUM. Treatment was attempted in 95 patients, and 91 patients received treatment. In the treated population (n = 91), the ORR was 36.3 % (95 % confidence interval [CI], 26.44-47.01), including 7.7 % of patients with a complete response. Thus, the study met its primary end point because the lower bound of the 95 % CI for ORR exceeded the upper bound (8.3 %) from the benchmark meta-analysis. The median DOR was 14 months, and the median OS was 20.5 months, with an OS of 80 % at 1 year. The median PFS was 9 months, with a PFS of 65 % at 6 months. The most common serious treatment-emergent adverse events were thrombocytopenia (15.8 %) and neutropenia (10.5 %), treated mostly on an outpatient basis with observation. No treatment-related deaths were observed. CONCLUSION: Treatment with melphalan/HDS provides a clinically meaningful response rate and demonstrates a favorable benefit-risk profile in patients with unresectable mUM (study funded by Delcath; ClinicalTrials.gov identifier: NCT02678572; EudraCT no. 2015-000417-44).
Asunto(s)
Antineoplásicos Alquilantes , Neoplasias Hepáticas , Melanoma , Melfalán , Neoplasias de la Úvea , Humanos , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/secundario , Melanoma/mortalidad , Melfalán/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Neoplasias de la Úvea/tratamiento farmacológico , Neoplasias de la Úvea/patología , Neoplasias de la Úvea/mortalidad , Anciano , Adulto , Tasa de Supervivencia , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Estudios de Seguimiento , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/uso terapéutico , Pronóstico , Anciano de 80 o más Años , Sistemas de Liberación de MedicamentosAsunto(s)
Antineoplásicos Alquilantes , Neoplasias Encefálicas , Carmustina , Glioblastoma , Isocitrato Deshidrogenasa , Glioblastoma/tratamiento farmacológico , Glioblastoma/cirugía , Humanos , Carmustina/administración & dosificación , Isocitrato Deshidrogenasa/genética , Neoplasias Encefálicas/cirugía , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/administración & dosificación , AdultoAsunto(s)
Antineoplásicos Alquilantes , Melanoma , Melfalán , Neoplasias de la Úvea , Humanos , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/secundario , Melfalán/administración & dosificación , Neoplasias de la Úvea/tratamiento farmacológico , Neoplasias de la Úvea/patología , Antineoplásicos Alquilantes/administración & dosificación , Tasa de Supervivencia , Pronóstico , Estudios de Seguimiento , Sistemas de Liberación de Medicamentos , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológicoAsunto(s)
Antineoplásicos Alquilantes , Neoplasias Encefálicas , Carmustina , Glioblastoma , Isocitrato Deshidrogenasa , Humanos , Glioblastoma/tratamiento farmacológico , Glioblastoma/cirugía , Neoplasias Encefálicas/cirugía , Isocitrato Deshidrogenasa/genética , Carmustina/administración & dosificación , Carmustina/efectos adversos , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/administración & dosificación , Adulto , Resultado del TratamientoRESUMEN
PURPOSE: It remains unclear whether combining carmustine wafer (CW) implantation with the standard treatment for adult-type diffuse gliomas is safe and has a prognostic impact. This study aimed to investigate the prognostic value and safety of CW implantation. METHODS: Adult patients with IDH-wild-type and -mutant gliomas, grades 3-4 treated with surgical resection, radiotherapy, and temozolomide chemotherapy between 2013 and 2023 were surveyed. CWs were implanted except in cases of intraoperative wide ventricle opening or marked preoperative brain swelling. For survival analyses, a case-matched dataset based on propensity score matching (PSM), including multiple factors (patient background, diagnosis, and extent of resection) was generated. Progression-free survival (PFS), overall survival (OS), and frequency of complications of CW implantation (brain edema, infection, and cerebrospinal fluid leakage) were compared between the CW and non-use groups. RESULTS: In total, 127 patients (75 in the CW use group and 52 in the non-use group) were enrolled. Regardless of stratification, no significant differences in PFS and OS were observed between the CW use and non-use groups. The frequency of postoperative brain edema was significantly higher in the CW use group than in the non-use group. An adjusted dataset containing 41 patients in the CW use and nonuse groups was generated. Even after PSM, CW implantation had no prognostic effect. CONCLUSIONS: CW implantation with standard treatment demonstrated little beneficial effect for the present strategy of CW use.
Asunto(s)
Antineoplásicos Alquilantes , Neoplasias Encefálicas , Carmustina , Glioma , Puntaje de Propensión , Humanos , Masculino , Femenino , Carmustina/administración & dosificación , Carmustina/efectos adversos , Carmustina/uso terapéutico , Glioma/tratamiento farmacológico , Persona de Mediana Edad , Neoplasias Encefálicas/cirugía , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/administración & dosificación , Adulto , Estudios Retrospectivos , Pronóstico , Estudios de Cohortes , Anciano , Implantes de Medicamentos , Tasa de Supervivencia , Estudios de SeguimientoRESUMEN
One key aspect of allogeneic hematopoietic cell transplantation (HCT) is pretransplant conditioning, balancing risk for relapse versus non-relapse mortality. Conditioning regimens with different alkylators at different doses can influence outcome, but data are missing for myelofibrosis, a challenging cohort of patients usually presenting at older age and with comorbidities. We evaluated in a multicenter retrospective study the comparative efficacy and safety of busulfan versus treosulfan in combination with fludarabine for myelofibrosis patients undergoing HCT. This study included 1115 patients (busulfan, n = 902; treosulfan, n = 213) receiving first HCT between 2005 and 2021. Patients were generally balanced for key patient characteristics. Overall survival at 4 years was 62% for the busulfan group versus 58% for the treosulfan group (p = .22). Impact on outcome was dose-dependent. Overall survival was 65% (95% CI, 61%-69%) for reduced intensity busulfan versus 69% (95% CI, 54%-84%) for reduced intensity treosulfan, 53% (95% CI, 44%-63%) for higher intensity busulfan, and 55% (95% CI, 46%-63%) for higher intensity treosulfan. Incidence of relapse was similar across intensity groups. In multivariable analysis, the hazard for death (with reduced intensity busulfan as reference) was 0.88 (95% CI, 0.39-2.01) for reduced intensity treosulfan (p = .77), 1.42 (95% CI, 0.96-2.10) for higher intensity busulfan (0.08), and 1.61 (95% CI, 1.14-2.26) for higher intensity treosulfan (p = .006). In terms of non-relapse mortality, comparison was not significantly different, while the hazard ratio for higher intensity treosulfan was 1.48 (95% CI, 0.98-2.23; p = .06). Here, we showed comparable outcomes and improved survival in myelofibrosis undergoing HCT with reduced intensity busulfan or treosulfan.
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Busulfano , Trasplante de Células Madre Hematopoyéticas , Mielofibrosis Primaria , Acondicionamiento Pretrasplante , Vidarabina , Busulfano/análogos & derivados , Busulfano/administración & dosificación , Busulfano/uso terapéutico , Humanos , Mielofibrosis Primaria/terapia , Mielofibrosis Primaria/mortalidad , Mielofibrosis Primaria/tratamiento farmacológico , Persona de Mediana Edad , Masculino , Femenino , Acondicionamiento Pretrasplante/métodos , Estudios Retrospectivos , Anciano , Adulto , Vidarabina/análogos & derivados , Vidarabina/administración & dosificación , Vidarabina/uso terapéutico , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/administración & dosificación , Adulto JovenRESUMEN
PURPOSE: The complex strategy of hypo-fractionated radiotherapy (HFRT) in combination with an immune checkpoint inhibitor (ICI) can stimulate a potential systemic antitumor response; however, the abscopal effect is always precluded by the tumor microenvironment, which may limit sufficient T-cell infiltration of distant nonirradiated tumors for certain kinds of inhibitory factors, such as regulatory T-cells (Tregs). Additionally, low-dose cyclophosphamide (LD-CYC) can specifically kill regulatory Tregs and strongly synergize antigen-specific immune responses, which could promote an abscopal effect. MATERIALS AND METHODS: We explored whether a triple regimen consisting of HFRT, ICI, and LD-CYC could achieve a better systemic antitumor response in bilateral mouse tumor models. RESULT: Our data demonstrate that LD-CYC combined with HFRT and antiprogrammed cell death ligand 1 (PDL-1) therapy could enhance the abscopal effect than only HFRT/antiPDL-1 or HFRT alone. Surprisingly, repeat CYC doses cannot further restrain tumor proliferation but can prolong murine overall survival, as revealed by the major pathologic responses. These results are associated with increased CD8 + effector T-cell infiltration, although LD-CYC did not upregulate PDL-1 expression in the tumor. CONCLUSIONS: Compared with traditional strategies, for the first time, we demonstrated that a triple treatment strategy remarkably increased the number of radiation-induced tumor-infiltrating CD8 + T-cells, effectively decreasing infiltrating Tregs, and promoting an abscopal effect. Thus, we describe a novel and effective therapeutic approach by combining multiple strategies to target several tumor-mediated immune inhibitory mechanisms.
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Ciclofosfamida , Inhibidores de Puntos de Control Inmunológico , Linfocitos T Reguladores , Microambiente Tumoral , Animales , Ciclofosfamida/farmacología , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Ratones , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/efectos de la radiación , Microambiente Tumoral/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/efectos de la radiación , Femenino , Terapia Combinada , Modelos Animales de Enfermedad , Melanoma Experimental/patología , Melanoma Experimental/inmunología , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/radioterapia , Radiación Ionizante , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/administración & dosificación , Ratones Endogámicos C57BL , Humanos , Línea Celular TumoralRESUMEN
PURPOSE: Percutaneous hepatic perfusion with melphalan (M-PHP) is a minimally invasive therapy with proven efficacy in patients with uveal melanoma (UM) liver metastases. M-PHP is associated with a short hospital admission time and limited systemic side effects. In this study, we assessed quality of life (QoL) in UM patients treated with M-PHP. MATERIALS AND METHODS: A prospective, single-center study including 24 patients treated with M-PHP for UM metastases to the liver. QoL questionnaires were collected at baseline, on day 2/3 after M-PHP, and on day 7 and day 21 after M-PHP, according to study protocol. The results were scored according to EORTC-QLQ C30 global health status (GHS), functional scales, and symptom scales. The difference in scores at baseline and subsequent time points was analyzed with the Wilcoxon signed-rank test and multiple testing Bonferroni correction. Adverse events (AE) were registered up to 30 days after M-PHP according to CTCAE v5.0. RESULTS: Twenty-four patients (14 males; median age 63.0 years) completed 96 questionnaires. Most scores on all scales declined on day 2/3 after M-PHP. On day 21 after M-PHP, 12 out of 15 scores returned to baseline, including median GHS scores. Three variables were significantly worse on day 21 compared to baseline: fatigue (6-33; p = 0.002), physical functioning (100 vs 86.7; p = 0.003), and role functioning (100 vs 66.7; p = 0.001). Grade 3/4 AEs consisted mainly of hematological complications, such as leukopenia and thrombopenia. CONCLUSION: M-PHP causes fatigue and a decline in physical and role functioning in the 1st weeks after treatment, but GHS returns to baseline levels within 21 days. LEVEL OF EVIDENCE 3: Cohort study.
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Neoplasias Hepáticas , Melanoma , Melfalán , Calidad de Vida , Neoplasias de la Úvea , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Prospectivos , Melanoma/secundario , Melanoma/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/terapia , Encuestas y Cuestionarios , Anciano , Melfalán/administración & dosificación , Melfalán/uso terapéutico , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/administración & dosificación , Quimioterapia del Cáncer por Perfusión Regional/métodos , Adulto , Resultado del TratamientoRESUMEN
Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for treatment of relapsed/refractory mantle cell lymphoma (MCL). During a fludarabine shortage, we used bendamustine as an alternative to standard cyclophosphamide/fludarabine (cy/flu) lymphodepletion (LD) prior to brexu-cel. We assessed MCL patient outcomes as well as CAR T-cell expansion and persistence after brexu-cel following bendamustine or cy/flu LD at our center. This was a retrospective single institution study that utilized prospectively banked blood and tissue samples. Clinical efficacy was assessed by 2014 Lugano guidelines. CAR T-cell expansion and persistence in peripheral blood were assessed on day 7 and at ≥month 6 for patients with available samples. Seventeen patients received bendamustine and 5 received cy/flu. For the bendamustine cohort, 14 (82%) received bridging therapy and 4 (24%) had CNS involvement. Fifteen patients (88%) developed CRS with 4 (24%) ≥grade 3 events. Six (35%) patients developed ICANS with 4 (24%) events ≥grade 3. No patient had ≥grade 3 cytopenias at day 90. Best objective (BOR) and complete response (CRR) rates were 82% and 65%, respectively. At 24.5 months median follow-up, 12-month progression-free survival (PFS) was 45%, 24-month PFS was 25%, and median duration of response was 19 months. Median OS was not reached. BOR was 25% (1/4) for patients with CNS involvement. CAR transgene expansion after bendamustine LD was observed on day 7 in all (4/4) patients tested and persisted at ≥6 months (2/2), regardless of response. Bendamustine LD before brexu-cel for MCL is feasible and safe with a lower frequency and shorter duration of cytopenias than reported for cy/flu. Both CAR T-cell expansion and persistence were observed after bendamustine LD. Outcomes appear comparable to the real world outcomes reported with cy/flu LD.
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Clorhidrato de Bendamustina , Inmunoterapia Adoptiva , Linfoma de Células del Manto , Humanos , Clorhidrato de Bendamustina/uso terapéutico , Clorhidrato de Bendamustina/administración & dosificación , Linfoma de Células del Manto/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Inmunoterapia Adoptiva/métodos , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Vidarabina/administración & dosificación , Adulto , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/administración & dosificación , Antígenos CD19/inmunología , Resultado del TratamientoRESUMEN
OBJECTIVE: The study was aimed at formulating temozolomide (TMZ) loaded gelatin nanoparticles (GNPs) encapsulated into polyvinyl alcohol (PVA) nanofibers (TMZ-GNPs-PVA NFs) as the nano-in-nanofiber delivery system. The secondary objective was to explore the sustained releasing ability of this system and to assess its enhanced cellular uptake against U87MG glioma cells in vitro. SIGNIFICANCE: Nano-in-nanofibers are the emerging drug delivery systems for treating a wide range of diseases including cancers as they overcome the challenges experienced by nanoparticles and nanofibers alone. METHODS: The drug-loaded GNPs were formulated by one-step desolvation method. The Design of Experiments (DoE) was used to optimize nanoparticle size and entrapment efficiency. The optimized drug-loaded nanoparticles were then encapsulated within nanofibers using blend electrospinning technique. The U87MG glioma cells were used to investigate the uptake of the formulation. RESULTS: A 32 factorial design was used to optimize the mean particle size (145.7 nm) and entrapment efficiency (87.6%) of the TMZ-loaded GNPs which were subsequently ingrained into PVA nanofibers by electrospinning technique. The delivery system achieved a sustained drug release for up to seven days (in vitro). The SEM results ensured that the expected nano-in-nanofiber delivery system was achieved. The uptake of TMZ-GNPs-PVA NFs by cells was increased by a factor of 1.964 compared to that of the pure drug. CONCLUSION: The nano-in-nanofiber drug delivery system is a potentially useful therapeutic strategy for the management of glioblastoma multiforme.