RESUMEN
INTRODUCTION: High-dose methotrexate (HDMTX) use can be limited by the development of acute kidney injury (AKI). Early AKI detection is paramount to prevent further renal injury and irreversible toxicities. This study sought to determine whether early elimination patterns of MTX would be useful as a biomarker of AKI in HDMTX treatment. METHODS: This retrospective cohort study included two sites that collected ≥2 MTX levels within 16 h from completion of MTX infusion. Early levels were tagged and MTX elimination half-life (t½) were calculated from combinations of two of three different early time periods. Receiver operating characteristic (ROC) curves were synthesized for each elimination t½ (biomarker) with respect to AKI and delayed methotrexate elimination (DME); the biomarker with the highest area under the ROC curve (AUC) was tested in a multiple variable logistic regression model. RESULTS: Data from 169 patients who received a total of 556 courses of HDMTX were analyzed. ROC analysis revealed MTX elimination t½ calculated from the second and third time periods had the highest AUC for AKI at 0.62 (interquartile range [IQR] 0.56-0.69) and DME at 0.86 (IQR 0.73-1.00). After adjusting for age, sex, dose (mg/m2), infusion duration, HDMTX course, and baseline estimated glomerular filtration rate, it remained significant for AKI with an OR of 1.29 and 95% confidence interval of 1.03-1.65. CONCLUSION: Early MTX elimination t½ measured within 16 h of infusion completion was significantly associated with the development of AKI and serves as an early clearance biomarker that may identify patients who benefit from increased hydration, augmented leucovorin rescue, and glucarpidase administration.
Asunto(s)
Lesión Renal Aguda , Monitoreo de Drogas , Metotrexato , Humanos , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/inducido químicamente , Metotrexato/farmacocinética , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Metotrexato/uso terapéutico , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Monitoreo de Drogas/métodos , Anciano , Curva ROC , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/farmacocinética , Biomarcadores , AdultoRESUMEN
Fluoropyrimidines (FLs) [5-Fluorouracil, Capecitabine] are used in the treatment of several solid tumors. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for FL detoxification, and its deficiency could lead to severe, life-threatening or fatal toxicity after FL administration. Testing with a pharmacogenetic panel of four deleterious variants in the dihydropyrimidine dehydrogenase gene (DPYD) (DPYD*2A, DPYD*13, c.2846A > T, c.1129-5923C > G) prior to FL treatment, is recommended by scientific consortia (e.g., CPIC, DPWG) and drug regulatory agencies (e.g., EMA). However, this panel identifies < 20% of patients at risk of severe FL-related toxicity. Cumulative recent evidence highlights the potential clinical value of rare (minor allele frequency < 1%) and novel DPYD genetic variants for identifying an additional fraction of DPD-deficient patients at increased risk of severe FL-related toxicity. In this review, we aimed to comprehensively describe the available evidence regarding the potential clinical predictive role of novel and rare DPYD variants as toxicity markers in FL-treated patients, and to discuss the challenges and opportunities in tailoring FL treatment based upon clinical application of such markers. Although we must overcome existing barriers to the clinical implementation, the available data support that comprehensive assessment of the DPYD sequence, including rare and novel genetic variants, may significantly enhance the pre-emptive identification of at-risk patients, compared to the current targeted approach.
Asunto(s)
Dihidrouracilo Deshidrogenasa (NADP) , Medicina de Precisión , Humanos , Dihidrouracilo Deshidrogenasa (NADP)/genética , Fluorouracilo/uso terapéutico , Fluorouracilo/efectos adversos , Capecitabina/uso terapéutico , Capecitabina/efectos adversos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Antimetabolitos Antineoplásicos/uso terapéutico , Antimetabolitos Antineoplásicos/efectos adversosRESUMEN
Hypomethylating agent treatment for myeloid leukemia associated with Down syndrome (ML-DS) has been scarcely reported. Herein, we collected information on azacitidine treatment for ML-DS in Japan. Forty-eight cycles of azacitidine treatment were performed for 12 patients, including 11 relapsed or refractory (R/R) patients. In 40 cycles, azacitidine was used as monotherapy. No azacitidine-related death was observed. One cycle concurrently administered with methotrexate-based intrathecal therapy was discontinued due to toxicities. Only 4 of the 19 cycles given in non-remission achieved complete or partial remission. In conclusion, although most toxicities were acceptable, azacitidine monotherapy might be insufficient for R/R ML-DS cases.
Asunto(s)
Antimetabolitos Antineoplásicos , Azacitidina , Síndrome de Down , Leucemia Mieloide , Humanos , Síndrome de Down/complicaciones , Síndrome de Down/tratamiento farmacológico , Azacitidina/uso terapéutico , Azacitidina/efectos adversos , Masculino , Femenino , Estudios Retrospectivos , Antimetabolitos Antineoplásicos/uso terapéutico , Antimetabolitos Antineoplásicos/efectos adversos , Japón/epidemiología , Preescolar , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/complicaciones , Niño , Adolescente , Lactante , AdultoRESUMEN
BACKGROUND: The Alpe-DPD study (NCT02324452) demonstrated that prospective genotyping and dose-individualization using four alleles in DPYD (DPYD*2A/rs3918290, c.1236G > A/rs75017182, c.2846A > T/rs67376798 and c.1679 T > G/rs56038477) can mitigate the risk of severe fluoropyrimidine toxicity. However, this could not prevent all toxicities. The goal of this study was to identify additional genetic variants, both inside and outside DPYD, that may contribute to fluoropyrimidine toxicity. METHODS: Biospecimens and data from the Alpe-DPD study were used. Exon sequencing was performed to identify risk variants inside DPYD. In silico and in vitro analyses were used to classify DPYD variants. A genome-wide association study (GWAS) with severe fluoropyrimidine-related toxicity was performed to identify variants outside DPYD. Association with severe toxicity was assessed using matched-pair analyses for the exon sequencing and logistic, Cox, and ordinal regression analyses for GWAS. RESULTS: Twenty-four non-synonymous, frameshift, and splice site DPYD variants were detected in ten of 986 patients. Seven of these variants (c.1670C > T, c.1913 T > C, c.1925 T > C, c.506delC, c.731A > C, c.1740 + 1G > T, c.763 - 2A > G) were predicted to be deleterious. The carriers of either of these variants showed a trend towards a 2.14-fold (95% CI, 0.41-11.3, P = 0.388) increased risk of severe toxicity compared to matched controls (N = 30). After GWAS of 942 patients, no individual single nucleotide polymorphisms achieved genome-wide significance (P ≤ 5 × 10-8), however, five variants were suggestive of association (P < 5 × 10-6) with severe toxicity. CONCLUSIONS: Results from DPYD exon sequencing and GWAS analysis did not identify additional genetic variants associated with severe toxicity, which suggests that testing for single markers at a population level currently has limited clinical value. Identifying additional variants on an individual level is still promising to explain fluoropyrimidine-related severe toxicity. In addition, studies with larger samples sizes, in more diverse cohorts are needed to identify potential clinically relevant genetic variants related to severe fluoropyrimidine toxicity.
Asunto(s)
Dihidrouracilo Deshidrogenasa (NADP) , Humanos , Dihidrouracilo Deshidrogenasa (NADP)/genética , Femenino , Masculino , Persona de Mediana Edad , Estudio de Asociación del Genoma Completo , Mutación de Línea Germinal , Anciano , Polimorfismo de Nucleótido Simple , Adulto , Fluorouracilo/efectos adversos , Pirimidinas/efectos adversos , Antimetabolitos Antineoplásicos/efectos adversos , ExonesRESUMEN
PURPOSE: Patients with dihydropyrimidine dehydrogenase (DPD) deficiency are at high risk for severe and fatal toxicity from fluoropyrimidine (FP) chemotherapy. Pre-treatment DPYD testing is standard of care in many countries, but not the United States (US). This survey assessed pre-treatment DPYD testing approaches in the US to identify best practices for broader adoption. METHODS: From August to October 2023, a 22-item QualtricsXM survey was sent to institutions and clinicians known to conduct pre-treatment DPYD testing and broadly distributed through relevant organizations and social networks. Responses were analyzed using descriptive analysis. RESULTS: Responses from 24 unique US sites that have implemented pre-treatment DPYD testing or have a detailed implementation plan in place were analyzed. Only 33% of sites ordered DPYD testing for all FP-treated patients; at the remaining sites, patients were tested depending on disease characteristics or clinician preference. Almost 50% of sites depend on individual clinicians to remember to order testing without the assistance of electronic alerts or workflow reminders. DPYD testing was most often conducted by commercial laboratories that tested for at least the four or five DPYD variants considered clinically actionable. Approximately 90% of sites reported receiving results within 10 days of ordering. CONCLUSION: Implementing DPYD testing into routine clinical practice is feasible and requires a coordinated effort among the healthcare team. These results will be used to develop best practices for the clinical adoption of DPYD testing to prevent severe and fatal toxicity in cancer patients receiving FP chemotherapy.
Asunto(s)
Deficiencia de Dihidropirimidina Deshidrogenasa , Dihidrouracilo Deshidrogenasa (NADP) , Humanos , Estados Unidos , Dihidrouracilo Deshidrogenasa (NADP)/metabolismo , Deficiencia de Dihidropirimidina Deshidrogenasa/diagnóstico , Neoplasias/tratamiento farmacológico , Antimetabolitos Antineoplásicos/efectos adversos , Encuestas y Cuestionarios , Fluorouracilo/efectos adversos , Fluorouracilo/administración & dosificaciónRESUMEN
BACKGROUND: Despite common global usage, fluoropyrimidine (FP; 5-flurouracil and capecitabine)-related chemotherapy toxicity is poorly reported in the literature, with serious toxicity ranging from 10% to 40% and early toxicity (within 60 days of exposure) quoted at 14%. Data reflecting the incidence of Grades 3-5 FP-related toxicity in Australian cancer patients is scant, despite the significant impact of toxicity on patients (hospitalisations, intensive care unit (ICU) admissions and even death). AIMS: This retrospective audit evaluated Grades 3-5 toxicities in a contemporaneous cohort of 500 patients receiving FP chemotherapies within the Hunter-New England Local Health District from June 2020 to June 2022. Data were extracted from public hospital records and oncology-specific e-records to determine rates of toxicity and associated hospitalisations, intensive care admissions and deaths that occurred within 60 days of first exposure to FP chemotherapy-containing regimens. RESULTS: One hundred and fifty incidents of Grades 3-4 toxicity in the first 60 days led to 87 patients presenting to hospital (87/500, 17.4%). The most common serious toxicities were diarrhoea (39.3%), nausea and vomiting (22.7%) and febrile neutropaenia (10%). Four patients were admitted to the ICU, and four patients died of toxicity. Within the first 60 days, 22.2% of patients required treatment delays, 21.4% required dose reductions, and 7.8% of patients ceased treatment because of toxicities. DISCUSSION AND CONCLUSION: Our experience reflects international reports and is likely generalisable to the Australian population. These data are a basis to understand the potential benefits of precision medicine strategies such as pharmacogenomic screening to improve patient tolerability and the cost-effectiveness of FP chemotherapy prescribing.
Asunto(s)
Capecitabina , Fluorouracilo , Neoplasias , Humanos , Estudios Retrospectivos , Masculino , Femenino , Capecitabina/efectos adversos , Persona de Mediana Edad , Anciano , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Australia/epidemiología , Neoplasias/tratamiento farmacológico , Adulto , Hospitalización/estadística & datos numéricos , Antimetabolitos Antineoplásicos/efectos adversos , Anciano de 80 o más Años , Diarrea/inducido químicamente , Diarrea/epidemiologíaRESUMEN
High-dose methotrexate (HD-MTX) is used in the treatment of children with central nervous system (CNS) tumors; however, toxicity information is limited. We characterized toxicities following 102 administrations of HD-MTX (4.6-13.5 g/m2) infused over 4 or 24 h in 38 children with a CNS tumor before 6 years of age (2010-2020). Delayed clearance of methotrexate occurred following 24% of infusions. Common Terminology Criteria for Adverse Events v5 grade 2-3 mucositis was observed in 47% of individuals, Grade 4 neutropenia in 76%, and grade 3-4 thrombocytopenia in 58%. No neurotoxicity was observed. HD-MTX can be safely used with supportive care and monitoring.
Asunto(s)
Antimetabolitos Antineoplásicos , Neoplasias del Sistema Nervioso Central , Metotrexato , Humanos , Metotrexato/efectos adversos , Metotrexato/administración & dosificación , Femenino , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Masculino , Preescolar , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/administración & dosificación , Lactante , Niño , Estudios de Seguimiento , Estudios Retrospectivos , Pronóstico , Mucositis/inducido químicamente , Neutropenia/inducido químicamenteRESUMEN
We present two cases of metastatic colorectal cancer where a liver injury developed while receiving capecitabine. In both cases, the patients were switched from oral capecitabine to a continuous intravenous 5-fluorouracil infusion and were able to continue treatment without a relapse of hepatotoxicity.
Asunto(s)
Antimetabolitos Antineoplásicos , Capecitabina , Enfermedad Hepática Inducida por Sustancias y Drogas , Neoplasias Colorrectales , Humanos , Capecitabina/efectos adversos , Capecitabina/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Masculino , Persona de Mediana Edad , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Femenino , Fluorouracilo/efectos adversos , Fluorouracilo/administración & dosificación , Anciano , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológicoRESUMEN
BACKGROUND AND AIMS: The cardiotoxicity related to 5-Fluorouracil (5-FU) in cancer patients has garnered widespread attention. The systemic immune-inflammation index (SII) has recently been identified as a novel predictive marker for the development of cardiovascular illnesses in individuals without pre-existing health conditions. However, it remains unclear whether the levels of SII are linked to cardiotoxicity related to 5-FU. This retrospective study aims to fill this knowledge gap by examining the correlation between SII and cardiotoxicity related to 5-FU in a colorectal cancer cohort. METHODS: The study comprised colorectal cancer patients who received 5-FU-based chemotherapy at the affiliated cancer hospital of Guizhou Medical University between January 1, 2018 and December 31, 2020. After adjustment for confounders and stratification by tertiles of the interactive factor, linear regression analyses, curve fitting and threshold effect analyses were conducted. RESULTS: Of the 754 patients included final analysis, approximately 21% (n = 156) of them ultimately experienced cardiotoxicity related to 5-FU. Monocytes (M) was found as an influential element in the interaction between SII and cardiotoxicity related to 5-FU. In the low tertile of M (T1: M ≤ 0.38 × 109/L), increasing log SII was positively correlated with cardiotoxicity related to 5-FU (Odds Ratio [OR], 8.04; 95% confidence interval [95%CI], 1.68 to 38.56). However, a curvilinear relationship between log SII and cardiotoxicity was observed in the middle tertile of M (T2: 0.38 < M ≤ 0.52 × 109/L). An increase in log SII above 1.37 was shown to be associated with a decreased risk of cardiotoxicity (OR, 0.14; 95%CI, 0.02 to 0.88), indicating a threshold effect. In the high tertile of M (T3: M > 0.52 × 109/L), there was a tendency towards a negative linear correlation between the log SII and cardiotoxicity was observed (OR, 0.85; 95%CI, 0.37 to 1.98). CONCLUSION: Our findings suggest that SII may serve as a potential biomarker for predicting cardiotoxicity related to 5-FU in colorectal cancer patients. SII is an independent risk factor for cardiotoxicity related to 5-FU with low monocytes levels (T1). Conversely, in the middle monocytes levels (T2), SII is a protective factor for cardiotoxicity related to 5-FU but with a threshold effect.
Asunto(s)
Cardiotoxicidad , Neoplasias Colorrectales , Fluorouracilo , Humanos , Fluorouracilo/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/inmunología , Masculino , Femenino , Persona de Mediana Edad , Cardiotoxicidad/etiología , Estudios Retrospectivos , Anciano , Inflamación , Antimetabolitos Antineoplásicos/efectos adversos , Monocitos/inmunología , Monocitos/efectos de los fármacos , AdultoAsunto(s)
Antimetabolitos Antineoplásicos , Neoplasias de los Conductos Biliares , Colangiocarcinoma , Desoxicitidina , Gemcitabina , Hiperamonemia , Humanos , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/complicaciones , Hiperamonemia/inducido químicamente , Desoxicitidina/análogos & derivados , Desoxicitidina/efectos adversos , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/complicaciones , Antimetabolitos Antineoplásicos/efectos adversos , Masculino , Persona de Mediana Edad , Anciano , FemeninoRESUMEN
BACKGROUND: Concurrent chemoradiotherapy now represents the standard of care in locally advanced unresectable squamous cell carcinoma of the head and neck, and the administration of cisplatin in triweekly or weekly schedules is the most commonly used chemotherapeutic agent. However, the chemotherapeutic agent and its scheduling with radiation is still an area of investigation with safer toxicity profile and better response rates. Gemcitabine is a potent radiosensitizer, and non-cytotoxic concentration results in decreased systemic toxicity while maintaining radiosensitization properties. Furthermore, data are emerging for low-dose and long-duration infusion where this strategy is found to be effective and a safe alternative to standard brief infusion. Based on these two strategies, that is, non-cytotoxic concentration with long duration, we have explored the unique possibility of further lowering the toxicity profile without compromising the efficacy. METHOD: Eligible patients of locally advanced unresectable squamous cell carcinoma of the head and neck underwent radiation treatment with concurrent gemcitabine. A total dose of 70 Gy in 35 fractions over a period of seven weeks with conventional fractionation schedule was delivered with cord off after 44 Gy. Concurrent gemcitabine was administered intravenously for over two hours once a week, 1-2 h before radiation and for seven consecutive weeks at 50 mg/m2. RESULT: Fifty-two patients was enrolled in this study, out of which 41 completed the treatment. Fifty-nine percent completed treatment within seven weeks. Sixty-four percent were found to have received more than five cycles. Mean follow-up of patients was found to be 4.9 months. Sixty-eight percent had complete response. Stage III patients achieved more complete response compared to stage IV. There was no site-wise difference in achieving complete response. Patients who have received less than five chemo cycles or completed the treatment in more than seven weeks had less complete response. Sixty-one percent had severe mucositis while 39% developed mild/moderate mucositis. Considering skin toxicity, 80% were found to have mild/moderate skin toxicity, while only 20% suffered from severe grades of skin toxicity. CONCLUSION: Gemcitabine in low-dose and long-duration infusion is a potent radiosensitizer with safer hematological toxicity and manageable local toxicities.
Asunto(s)
Carcinoma de Células Escamosas , Quimioradioterapia , Desoxicitidina , Gemcitabina , Neoplasias de Cabeza y Cuello , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Desoxicitidina/análogos & derivados , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Quimioradioterapia/métodos , Quimioradioterapia/efectos adversos , Neoplasias de Cabeza y Cuello/terapia , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Persona de Mediana Edad , Masculino , Femenino , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Anciano , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Adulto , Resultado del Tratamiento , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/uso terapéutico , Antimetabolitos Antineoplásicos/efectos adversos , Esquema de Medicación , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Estadificación de NeoplasiasAsunto(s)
Antimetabolitos Antineoplásicos , Etiquetado de Medicamentos , Fluorouracilo , Humanos , Fluorouracilo/efectos adversos , Etiquetado de Medicamentos/normas , Antimetabolitos Antineoplásicos/efectos adversos , Estados Unidos , United States Food and Drug Administration , Seguridad del Paciente/normasRESUMEN
Methotrexate is a critical component of curative chemotherapy for pediatric acute lymphoblastic leukemia (ALL), but is associated with neurotoxicity. Information on long-term outcomes following an acute neurotoxic event is limited. Therefore, this report compares neurocognitive performance more than 12 months post diagnosis (mean = 4 years) between ALL patients with (n = 25) and without (n = 146) a history of acute neurotoxicity. Compared to children with no documented on-treatment neurotoxic event, children who experienced a neurotoxic event during treatment exhibited poorer performance on measures of fine motor function (p = .02) and attention (p = .02). Children with ALL who experience acute neurotoxicity may be candidates for early neuropsychological screening and intervention.
Asunto(s)
Antimetabolitos Antineoplásicos , Metotrexato , Síndromes de Neurotoxicidad , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Metotrexato/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Femenino , Masculino , Síndromes de Neurotoxicidad/etiología , Niño , Preescolar , Antimetabolitos Antineoplásicos/efectos adversos , Adolescente , Estudios de Seguimiento , Pruebas Neuropsicológicas , PronósticoRESUMEN
INTRODUCTION: This is the first report of a patient who developed cardiogenic shock after receiving oral chemotherapy with capecitabine and was treated with venoarterial extracorporeal membrane oxygenation combined with continuous renal replacement therapy. CLINICAL FINDINGS: A 58-year-old man developed an arrhythmia that rapidly progressed to cardiogenic shock and cardiac arrest after receiving oral capecitabine tablets to treat a rectal malignancy. INTERVENTIONS: The patient was treated with venoarterial extracorporeal membrane oxygenation in combination with continuous renal replacement therapy. OUTCOME: The patient made a full recovery and was discharged from the hospital. CONCLUSION: The use of comprehensive supportive treatments such as extracorporeal membrane oxygenation combined with continuous renal replacement therapy in patients with capecitabine-induced cardiac arrest can rapidly reduce drug concentrations, eliminate harmful substances, and improve the prognosis.
Asunto(s)
Antimetabolitos Antineoplásicos , Capecitabina , Oxigenación por Membrana Extracorpórea , Paro Cardíaco , Humanos , Masculino , Persona de Mediana Edad , Capecitabina/efectos adversos , Capecitabina/uso terapéutico , Paro Cardíaco/inducido químicamente , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/uso terapéutico , Terapia de Reemplazo Renal Continuo , Choque Cardiogénico/inducido químicamente , Choque Cardiogénico/terapia , Resultado del Tratamiento , Neoplasias del Recto/tratamiento farmacológicoRESUMEN
BACKGROUND: Locally advanced pancreatic cancer (LAPC) comprises 40% of pancreatic cancer diagnoses and has a relatively poor prognosis. Trans-arterial micro perfusion (TAMP)-mediated chemotherapy delivery to the primary tumor is a novel approach worthy of investigation. The RR1 (dose escalation) and RR2 (observational) studies examined the safety and preliminary efficacy of TAMP-delivered gemcitabine for LAPC. PATIENTS AND METHODS: RR1 and RR2 data were pooled. Both studies enrolled patients with LAPC with histologically confirmed adenocarcinoma. Participant data, including age, sex, race, stage, previous treatments, toxicity, disease progression, and death, were collected. Median number of cycles and average treatment dosage were calculated. Overall survival (OS) was determined for the whole group and separately for patients who received and did not receive previous treatments. Aims of the analysis were to assess procedure safety, OS, and evaluate factors associated with OS. RESULTS: The median age of the 43 patients enrolled in RR1 and RR2 was 72 years (range, 51-88 years). Median OS for the 35 eligible patients with stage III disease was 12.6 months (95% CI, 2.1-54.2 months). Previous chemoradiation was associated with significantly longer OS [27.1 months (95% CI, 8.4-40.6 months)] compared to previous systemic chemotherapy [14.6 months (95% CI, 6.4-54.2 months)] or no prior treatment [7.0 months (95% CI, 2.1-35.4 months)] (Pâ <â .001). The most common adverse events were GI related (abdominal pain, emesis, and vomiting); the most common grade 3 toxicity was sepsis. CONCLUSION: Study results indicate that TAMP-mediated gemcitabine delivery in patients with LAPC is potentially safe, feasible, and provides potential clinical benefits. CLINICAL TRIAL REGISTRATION: NCT02237157 (RR1) and NCT02591082 (RR2).
Asunto(s)
Desoxicitidina , Gemcitabina , Neoplasias Pancreáticas , Humanos , Desoxicitidina/análogos & derivados , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Desoxicitidina/efectos adversos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Persona de Mediana Edad , Anciano , Femenino , Masculino , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/uso terapéutico , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patologíaRESUMEN
INTRODUCTION: Severe cutaneous adverse reactions (SCARs) arising from drug interactions can carry life-threatening implications and result in lasting effects. SCARs can be triggered by various factors, with trimethoprim/sulfamethoxazole identified as a primary culprit. Anticonvulsants and antineoplastic agents have been noted as secondary triggers. Notably, antineoplastics linked to SCARs include immunomodulatory agents. The higher mortality rates among cancer patients with SCARs underscore the significance of comprehending cancer--specific risk factors. Our objective is to present the case of a boy with acute lymphocytic leukemia (ALL) who developed Stevens-Johnson syndrome (SJS) following MTX treatment. CASE REPORT: We present the case of a three-year-old male patient diagnosed with ALL who developed Stevens-Johnson syndrome (SJS) subsequent to the administration of MTX, following the "BFM 2009" protocol. He had undergone intrathecal MTX administration on six previous occasions. Our patient received IVIG at a dose of 2g/kg along with steroids, resulting in partial clinical improvement after 21 days. An innovative protocol was developed, involving IVIG before MTX infusion and dexamethasone before MTXi, with folinic acid rescue. Intravenous immunoglobulin (IVIG) mitigates SJS/TEN via type IV hypersensitivity down-regulation and apoptosis curbing. CONCLUSION: As far as we know, the prophylactic use of IVIG to counteract SCARs in a pediatric leukemia patient represents uncharted territory. Moreover, research into the immune system dynamics within these patients and the preservation of indispensable treatments should involve allergist-immunologists as part of the multidisciplinary team attending to neoplastic conditions.
Asunto(s)
Metotrexato , Leucemia-Linfoma Linfoblástico de Células Precursoras , Síndrome de Stevens-Johnson , Humanos , Masculino , Síndrome de Stevens-Johnson/tratamiento farmacológico , Síndrome de Stevens-Johnson/etiología , Síndrome de Stevens-Johnson/diagnóstico , Preescolar , Metotrexato/uso terapéutico , Metotrexato/efectos adversos , Metotrexato/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunoglobulinas Intravenosas/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/uso terapéutico , Dexametasona/administración & dosificación , Dexametasona/uso terapéuticoAsunto(s)
Desoxicitidina , Gemcitabina , Neutropenia , Trombocitopenia , Pez Cebra , Pez Cebra/genética , Desoxicitidina/análogos & derivados , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Animales , Trombocitopenia/inducido químicamente , Neutropenia/inducido químicamente , Neutropenia/tratamiento farmacológico , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/uso terapéuticoRESUMEN
PURPOSE: Fluoropyrimidine-related toxicity and mortality risk increases significantly in patients carrying certain DPYD genetic variants with standard dosing. We implemented DPYD genotyping at a multisite cancer center and evaluated its impact on dosing, toxicity, and hospitalization. METHODS: In this prospective observational study, patients receiving (reactive) or planning to receive (pretreatment) fluoropyrimidine-based chemotherapy were genotyped for five DPYD variants as standard practice per provider discretion. The primary end point was the proportion of variant carriers receiving fluoropyrimidine modifications. Secondary end points included mean relative dose intensity, fluoropyrimidine-related grade 3+ toxicities, and hospitalizations. Fisher's exact test compared toxicity and hospitalization rates between pretreatment carriers, reactive carriers, and wild-type patients. Univariable and multivariable logistic regression identified factors associated with toxicity and hospitalization risk. Kaplan-Meier methods estimated time to event of first grade 3+ toxicity and hospitalization. RESULTS: Of the 757 patients who received DPYD genotyping (median age 63, 54% male, 74% White, 19% Black, 88% GI malignancy), 45 (5.9%) were heterozygous carriers. Fluoropyrimidine was modified in 93% of carriers who started treatment. In 442 patients with 3-month follow-up, 64%, 31%, and 30% of reactive carriers, pretreatment carriers, and wild-type patients had grade 3+ toxicity, respectively (P = .085); 64%, 25%, and 13% were hospitalized (P < .001). Reactive carriers had 10-fold higher odds of hospitalization compared with wild-type patients (P = .001), whereas no significant difference was noted between pretreatment carriers and wild-type patients. Time-to-event of toxicity and hospitalization were significantly different between genotype groups (P < .001), with reactive carriers having the earliest onset and highest incidence. CONCLUSION: DPYD genotyping prompted fluoropyrimidine modifications in most carriers. Pretreatment testing reduced toxicities and hospitalizations compared with reactive testing, thus normalizing the risk to that of wild-type patients, and should be considered standard practice.
Asunto(s)
Dihidrouracilo Deshidrogenasa (NADP) , Genotipo , Hospitalización , Humanos , Masculino , Femenino , Dihidrouracilo Deshidrogenasa (NADP)/genética , Persona de Mediana Edad , Hospitalización/estadística & datos numéricos , Estudios Prospectivos , Anciano , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/uso terapéutico , Instituciones Oncológicas , AdultoRESUMEN
BACKGROUND: Pre-treatment DPYD screening is mandated in the UK and EU to reduce the risk of severe and potentially fatal fluoropyrimidine-related toxicity. Four DPYD gene variants which are more prominently found in Europeans are tested. METHODS: Our systematic review in patients of non-European ancestry followed PRISMA guidelines to identify relevant articles up to April 2023. Published in silico functional predictions and in vitro functional data were also extracted. We also undertook in silico prediction for all DPYD variants identified. RESULTS: In 32 studies, published between 1998 and 2022, 53 DPYD variants were evaluated in patients from 12 countries encompassing 5 ethnic groups: African American, East Asian, Latin American, Middle Eastern, and South Asian. One of the 4 common European DPYD variants, c.1905+1G>A, is also present in South Asian, East Asian and Middle Eastern patients with severe fluoropyrimidine-related toxicity. There seems to be relatively strong evidence for the c.557A>G variant, which is found in individuals of African ancestry, but is not currently included in the UK genotyping panel. CONCLUSION: Extending UK pre-treatment DPYD screening to include variants that are present in some non-European ancestry groups will improve patient safety and reduce race and health inequalities in ethnically diverse societies.