RESUMEN
Cancer in neonates and infants is a rare but challenging entity. Treatment is complicated by marked physiological changes during the first year of life, excess rates of toxicity, mortality, and late effects. Dose optimisation of chemotherapeutics may be an important step to improving outcomes. Body size-based dosing is used for most anticancer drugs used in infants. However, dose regimens are generally not evidence based, and dosing strategies are frequently inconsistent between tumour types and treatment protocols. In this review, we collate available pharmacological evidence supporting dosing regimens in infants for a wide range of cytotoxic drugs. A systematic review was conducted, and available data ranked by a level of evidence (1-5) and a grade of recommendation (A-D) provided on a consensus basis, with recommended dosing approaches indicated as appropriate. For 9 of 29 drugs (busulfan, carboplatin, cyclophosphamide, daunorubicin, etoposide, fludarabine, isotretinoin, melphalan and vincristine), grade A was scored, indicating sufficient pharmacological evidence to recommend a dosing algorithm for infants. For busulfan and carboplatin, sufficient data were available to recommend therapeutic drug monitoring in infants. For eight drugs (actinomycin D, blinatumomab, dinutuximab, doxorubicin, mercaptopurine, pegaspargase, thioguanine and topotecan), some pharmacological evidence was available to guide dosing (graded as B). For the remaining drugs, including commonly used agents such as cisplatin, cytarabine, ifosfamide, and methotrexate, pharmacological evidence for dosing in infants was limited or non-existent: grades C and D were scored for 10 and 2 drugs, respectively. The review provides clinically relevant evidence-based dosing guidance for cytotoxic drugs in neonates and infants.
Asunto(s)
Antineoplásicos , Busulfano , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino , Etopósido , Humanos , Lactante , Recién NacidoRESUMEN
BACKGROUND: The anticancer drug vincristine is associated with potentially dose-limiting side-effects, including neurotoxicity and myelosuppression. However, there currently exists a lack of published clinical pharmacology data relating to its use in neonate and infant patients. We report a study investigating vincristine dosing and drug exposure, alongside the feasibility and impact of a therapeutic drug monitoring treatment approach, in this challenging patient population. PATIENTS AND METHODS: Vincristine pharmacokinetic data from a total of 57 childhood cancer patients, including 26 neonates and infants, were used to characterise a population pharmacokinetic model. Vincristine was administered at doses of 0.02-0.05 mg/kg or 0.75-1.5 mg/m2 in neonates and infants aged <1 year or ≤12 kg and doses of 1.5 mg/m2 in older children. RESULTS: A two-compartment model provided the best fit for the population analysis. There was no significant difference in vincristine clearance normalised for body surface area between neonates/infants and older children. Lower doses administered to neonates and infants resulted in significantly lower drug exposures (area under the curve [AUC]), compared with older children (p = 0.047). Vincristine doses of <0.05 mg/kg in neonates and infants resulted in significantly lower AUC values than observed in those receiving doses of ≥0.05 mg/kg (p ≤ 0.0001). Therapeutic drug monitoring was shown to be feasible, effective and well tolerated in neonates and infants experiencing suboptimal drug exposures. CONCLUSION: Doses of <0.05 mg/kg should not be used in neonate and infant patients because of a high risk of patients experiencing potentially suboptimal drug exposures. Therapeutic drug monitoring approaches in neonates and infants are supported by the data generated, with a proposed target therapeutic window of 50-100 µg/l∗h.
Asunto(s)
Antineoplásicos , Neoplasias , Adolescente , Área Bajo la Curva , Niño , Monitoreo de Drogas/métodos , Humanos , Lactante , Recién Nacido , Neoplasias/inducido químicamente , Neoplasias/tratamiento farmacológico , Vincristina/efectos adversosRESUMEN
BACKGROUND: Patella resurfacing is commonly performed during total knee arthroplasty; however, determining the appropriate patellar thickness remains a challenge. The purpose of this study was to evaluate the role of post-TKA patellar thickness on knee extensor strength and biomechanical joint loading forces during walking and stair negotiation. METHODS: Fifteen patients (21 knees) underwent gait analysis prior to TKA and post-TKA at six weeks, three months, six months, and one year. Knee extensor strength and biomechanics were collected during level walking and stair negotiation and analyzed using Pearson correlation coefficients. RESULTS: Knee extensor strength was positively correlated to patellar thickness at three months and one year post-TKA (pâ¯≤â¯.05). During walking, no significant correlations were present. During stair ascent, there was a positive correlation between patellar thickness and peak knee flexion angle one year post-TKA (pâ¯≤â¯.05). During stair descent, there was a positive correlation between patellar thickness and maximum vertical ground reaction forces at one year post-TKA (pâ¯≤â¯.01). CONCLUSIONS: The loss of patellar thickness when compared to measured pre-resurfacing thickness was correlated with a decrease in knee extensor strength; however, changes in patellar thickness were not significantly correlated to biomechanical loading forces during walking. Increases in demand of activity increase the torque to the knee joint, which elicit increases in compensatory motions, likely reducing the extent to which differences in joint loading during stair negotiation may be attributable to changes in patellar thickness. Therefore, the effect of post-patellar thickness on patient function in primary TKA is limited.
Asunto(s)
Artroplastia de Reemplazo de Rodilla , Análisis de la Marcha , Rótula/patología , Anciano , Fenómenos Biomecánicos , Femenino , Humanos , Estudios Longitudinales , Masculino , Osteoartritis de la Rodilla/cirugía , Rótula/cirugía , CaminataRESUMEN
BACKGROUND: In place of the mechanical axis (MA), the use of the variable tibiofemoral angle is frequently used to plan measured resection bony cuts during total knee arthroplasty (TKA). This angle, coupled with operator-dependent variability of intramedullary distal femoral cutting guides, has the potential for catastrophic outcomes. Therefore, a simpler, fixed femoral cut of 6° valgus may be more appropriate when direct measurement of the MA is not possible. METHODS: This was a retrospective study of 788 consecutive TKAs, in which the distal femoral cut was set to 6° valgus. The preoperative and 6-week postoperative MA were measured on hip-to-ankle radiographs. Data were evaluated as a group as well as grouped by preoperative deformity (MA < -3°, -3° < MA < 3°, 3° < MA). RESULTS: Following TKA, MA alignment for all patients was 0.0° ± 2.3° (range, -7.0° to 8.0°). When grouped by pre-TKA alignment, 548 patients were considered varus (MA < -3°), 137 were neutral (-3° < MA < 3°), and 103 patients were valgus (3° < MA). When evaluating the post-TKA alignment achieved in the 3 groups, neutral alignment (-3° < MA < 3°) was established in 86.5% of varus patients, 86.1% of neutral patients, and 82.5% of valgus patients. CONCLUSION: A standard distal femoral cut of 6° resulted in a neutral MA in 86% of patients. While no single technique will be correct for all deformities, in the absence of sophisticated preoperative planning aids, this simple technique could provide a more reliable surgical technique than the measured tibiofemoral angle.
Asunto(s)
Artroplastia de Reemplazo de Rodilla/métodos , Fémur/cirugía , Articulación de la Rodilla/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Articulación de la Rodilla/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Radiografía , Estudios RetrospectivosRESUMEN
Various scaling methods are used when attempting to remove the influence of anthropometric differences on ground reaction forces (GRF) when comparing groups. Though commonly used, ratio scaling often results in an over-correction. Allometric scaling has previously been suggested for kinetic variables but its effectiveness in partialing out the effect of anthropometrics is unknown due to a lack of consistent application. This study examined the effectiveness of allometric scaling vertical, braking and propulsive GRF and loading rate for 84 males and 47 females while running at 4.0â¯m/s. Raw, unfiltered data were ratio scaled by body mass (BM), height (HT), and BM multiplied by HT (BM∗HT). Gender specific exponents for allometric scaling were determined by performing a log-linear (for BM and HT individually) or log-multilinear regression (BMHT). Pearson productmoment correlations were used to assess the effectiveness of each scaling method. Ratio scaling by BM, HT, or BM∗HT resulted in an over-correction of the data for most variables and left a considerable portion of the variance still attributable to anthropometrics. Allometric scaling by BM successfully removed the effect of BM and HT for all variables except for braking GRF in males and vertical GRF in females. However, allometric scaling for BMHT successfully removed the effect of BM and HT for all reactionary forces in both genders. Based on these results, allometric scaling for BMHT was the most appropriate scaling method for partialing out the effect of BM and HT on kinetic variables to allow for effective comparisons between groups or individuals.