Assessment of the Non-Technical Skills for Surgeons (NOTSS) framework in the USA.

BACKGROUND: Surgeons' non-technical skills are important for patient safety. The Non-Technical Skills for Surgeons assessment tool was developed in the UK and recently adapted to the US surgical context (NOTSS-US). The aim of this study was to evaluate the reliability and distribution of non-technical skill ratings given by attending (consultant) surgeons who underwent brief online training. METHODS: Attending surgeons across six specialties at a large US academic medical centre underwent a 10-min online training, then rated 60-s standardized videos of simulated operations. Intraclass correlation coefficient (ICC), and mean(s.d.) values for NOTSS-US ratings were determined for each non-technical skill category (score range 1-5, where 1 indicates poor, 3 average and 5 excellent) and for total NOTSS-US score (range 4-20; sum of 4 category scores). Outcomes were adjusted for rater characteristics including sex, specialty and clinical experience. RESULTS: A total of 8889 ratings were submitted by 81 surgeon raters on 30 simulated intraoperative videos. The mean(s.d.) total NOTSS-US score for all videos was 9·5(4·8) of 20. The within-video ICC for total NOTSS-US score was 0·64 (95 per cent c.i. 0·57 to 0·70). For individual non-technical skill categories, the ICC was highest for social skills (communication/teamwork: 0·63, 95 per cent c.i. 0·56 to 0·71; leadership: 0·64, 0·55 to 0·72) and lowest for cognitive skills (situation awareness: 0·54, 0·45 to 0·62; decision-making: 0·50, 0·41 to 0·59). Women gave higher total NOTSS-US scores than men (adjusted mean difference 0·93, 95 per cent c.i. 0·44 to 1·43; P = 0·001). CONCLUSION: After brief online training, the inter-rater reliability of the NOTSS-US assessment tool achieved moderate strength among trained surgeons rating simulated intraoperative videos.

ANTECEDENTES: Las habilidades no técnicas de los cirujanos (Non-Technical Skills for Surgeons, NOTSS) son importantes para la seguridad del paciente. La herramienta de evaluación de habilidades no técnicas para cirujanos se desarrolló en el Reino Unido y se adaptó recientemente al contexto quirúrgico de los Estados Unidos (NOTSS-US.). El objetivo de este estudio fue evaluar la fiabilidad y distribución de las calificaciones de habilidades no técnicas obtenidas por cirujanos adjuntos de cirugía (consultores) que recibieron una breve formación online. MÉTODOS: Cirujanos adjuntos de 6 especialidades en un gran centro universitario de Estados Unidos recibieron una formación online de 10 minutos de duración y seguidamente puntuaron vídeos estandarizados de operaciones simuladas de 60 minutos de duración. Se calcularon el coeficiente de correlación intraclase (intraclass correlation coefficient, ICC), la media y la desviación estándar (standard deviation, SD) para la puntuación de cada categoría de habilidad no técnica del NOTSS-US (rango 1-5, siendo 1 = pobre, 3 = promedio, 5 = excelente) y para la puntuación global de NOTSS-US (rango 4-20, suma de las puntuaciones de las cuatro categorías). Los resultados se ajustaron de acuerdo con las características del evaluador, incluyendo sexo, especialidad, experiencia clínica. RESULTADOS: En 30 videos intraoperatorios simulados, 81 cirujanos evaluadores proporcionaron 8.889 puntaciones. La puntuación media global de NOTSS-US para todos los vídeos fue de 9,5 sobre 20 (SD 4,8). El ICC de los vídeos para la puntuación global de NOTSS-US fue 0,64 (i.c. del 95% 0,57-0,70). Para las categorías individuales de habilidades no técnicas, el ICC más alto fue para las habilidades sociales (comunicación / trabajo en equipo: 0,63, (i.c. del 95% 0,56-0,71); liderazgo, 0,64 (i.c. del 95% 0,55-0,72)) y el más bajo para las habilidades cognitivas (conciencia de la situación 0,54 (i.c. del 95% 0,45-0,62); toma de decisiones 0,50 (i.c. del 95% 0,41-0,59)). Las evaluadoras femeninas presentaron puntuaciones globales de NOTSS-US más altas que los evaluadores masculinos (diferencia 0,93, i.c. del 95% 0,44-1,43; P = 0,001)). CONCLUSIÓN: Después de una breve formación online, la fiabilidad de la herramienta de evaluación NOTSS-US mostró una correlación moderada entre los cirujanos que puntuaron vídeos de simulaciones de intervenciones quirúrgicas.

Development and evaluation of a patient-centred measurement tool for surgeons' non-technical skills.

BACKGROUND: Non-technical skills are essential for safe and effective surgery. Several tools to assess surgeons' non-technical skills from the clinician's perspective have been developed. However, a reliable measurement tool using a patient-centred approach does not currently exist. The aim of this study was to translate the existing Non-Technical Skills for Surgeons (NOTSS) tool into a patient-centred evaluation tool. METHODS: Data were gathered from four cohorts of patients using an iterative four-stage mixed-methods research design. Exploratory and confirmatory factor analyses were performed to establish the psychometric properties of the tool, focusing on validity, reliability, usability and parsimony. RESULTS: Some 534 patients were recruited to the study. A total of 24 patient-centred non-technical skill items were developed in stage 1, and reduced to nine items in stage 2 using exploratory factor analysis. In stage 3, confirmatory factor analysis demonstrated that these nine items each loaded on to one of three factors, with excellent internal consistency: decision-making, leadership, and communication and teamwork. In stage 4, validity testing established that the new tool was independent of physician empathy and predictive of surgical quality. Surgical leadership emerged as the most dominant skill that patients could recognize and evaluate. CONCLUSION: A novel nine-item assessment tool has been developed. The Patients' Evaluation of Non-Technical Skills (PENTS) tool allows valid and reliable measurement of surgeons' non-technical skills from the patient perspective.

Systematic review of measurement tools to assess surgeons' intraoperative cognitive workload.

BACKGROUND: Surgeons in the operating theatre deal constantly with high-demand tasks that require simultaneous processing of a large amount of information. In certain situations, high cognitive load occurs, which may impact negatively on a surgeon's performance. This systematic review aims to provide a comprehensive understanding of the different methods used to assess surgeons' cognitive load, and a critique of the reliability and validity of current assessment metrics. METHODS: A search strategy encompassing MEDLINE, Embase, Web of Science, PsycINFO, ACM Digital Library, IEEE Xplore, PROSPERO and the Cochrane database was developed to identify peer-reviewed articles published from inception to November 2016. Quality was assessed by using the Medical Education Research Study Quality Instrument (MERSQI). A summary table was created to describe study design, setting, specialty, participants, cognitive load measures and MERSQI score. RESULTS: Of 391 articles retrieved, 84 met the inclusion criteria, totalling 2053 unique participants. Most studies were carried out in a simulated setting (59 studies, 70 per cent). Sixty studies (71 per cent) used self-reporting methods, of which the NASA Task Load Index (NASA-TLX) was the most commonly applied tool (44 studies, 52 per cent). Heart rate variability analysis was the most used real-time method (11 studies, 13 per cent). CONCLUSION: Self-report instruments are valuable when the aim is to assess the overall cognitive load in different surgical procedures and assess learning curves within competence-based surgical education. When the aim is to assess cognitive load related to specific operative stages, real-time tools should be used, as they allow capture of cognitive load fluctuation. A combination of both subjective and objective methods might provide optimal measurement of surgeons' cognition.

Construct and criterion validity testing of the Non-Technical Skills for Surgeons (NOTSS) behaviour assessment tool using videos of simulated operations.

BACKGROUND: Surgeons' non-technical skills are an important part of surgical performance and surgical education. The most widely adopted assessment tool is the Non-Technical Skills for Surgeons (NOTSS) behaviour rating system. Psychometric analysis of this tool to date has focused on inter-rater reliability and feasibility rather than validation. METHODS: NOTSS assessments were collected from two groups of consultant/attending surgeons in the UK and USA, who rated behaviours of the lead surgeon during a video-based simulated crisis scenario after either online or classroom instruction. The process of validation consisted of assessing construct validity, scale reliability and concurrent criterion validity, and undertaking a sensitivity analysis. Central to this was confirmatory factor analysis to evaluate the structure of the NOTSS taxonomy. RESULTS: Some 255 consultant surgeons participated in the study. The four-category NOTSS model was found to have robust construct validity evidence, and a superior fit compared with alternative models. Logistic regression and sensitivity analysis revealed that, after adjusting for technical skills, for every 1-point increase in NOTSS score of the lead surgeon, the odds of having a higher versus lower patient safety score was 2·29 times. The same pattern of results was obtained for a broad mix of surgical specialties (UK) as well as a single discipline (cardiothoracic, USA). CONCLUSION: The NOTSS tool can be applied in research and education settings to measure non-technical skills in a valid and efficient manner.

Non-technical skills of surgeons and anaesthetists in simulated operating theatre crises.

BACKGROUND: Deficiencies in non-technical skills (NTS) have been increasingly implicated in avoidable operating theatre errors. Accordingly, this study sought to characterize the impact of surgeon and anaesthetist non-technical skills on time to crisis resolution in a simulated operating theatre. METHODS: Non-technical skills were assessed during 26 simulated crises (haemorrhage and airway emergency) performed by surgical teams. Teams consisted of surgeons, anaesthetists and nurses. Behaviour was assessed by four trained raters using the Non-Technical Skills for Surgeons (NOTSS) and Anaesthetists' Non-Technical Skills (ANTS) rating scales before and during the crisis phase of each scenario. The primary endpoint was time to crisis resolution; secondary endpoints included NTS scores before and during the crisis. A cross-classified linear mixed-effects model was used for the final analysis. RESULTS: Thirteen different surgical teams were assessed. Higher NTS ratings resulted in significantly faster crisis resolution. For anaesthetists, every 1-point increase in ANTS score was associated with a decrease of 53·50 (95 per cent c.i. 31·13 to 75·87) s in time to crisis resolution (P < 0·001). Similarly, for surgeons, every 1-point increase in NOTSS score was associated with a decrease of 64·81 (26·01 to 103·60) s in time to crisis resolution in the haemorrhage scenario (P = 0·001); however, this did not apply to the difficult airway scenario. Non-technical skills scores were lower during the crisis phase of the scenarios than those measured before the crisis for both surgeons and anaesthetists. CONCLUSION: A higher level of NTS of surgeons and anaesthetists led to quicker crisis resolution in a simulated operating theatre environment.

Review of an established UK home phototherapy service 1998-2011: improving access to a cost-effective treatment for chronic skin disease.

OBJECTIVES: To review the Tayside home phototherapy service, including numbers of patients treated, diagnoses and outcomes, side-effects and safety, cost-effectiveness and absolute costs. To consider why home or outpatient phototherapy is not available to all patients who might benefit and how this could be addressed. STUDY DESIGN: Observational and cost analysis. METHODS: Analysis of the Tayside home phototherapy database 1998 and 2011, home phototherapy patient questionnaires, outcome data, costs and a comparison with outpatient phototherapy. Review of literature and current national guidelines for phototherapy, traditional systemic and biologic therapies for psoriasis. RESULTS: 298 courses of home narrowband UVB (NB-UVB) phototherapy were undertaken by 212 patients between 1998 and 2011, five courses in 1998 increasing to 36 in 2011. The main diagnoses treated were psoriasis (72%), atopic dermatitis (8%), and desensitization of photodermatosis (7%). For psoriasis, 74.5% achieved clearance or minimal residual activity in a median of 30 exposures (range 10-60). The estimated costs to the hospital ranged from £229 to £314 per course (£307 to £422 per effective course for psoriasis), compared with £114 for out-patient therapy (£149 per effective course for psoriasis). The total cost to society (hospital and patient costs) is around £410 per course, compared to an estimated £550 for outpatient therapy for this group of patients. Treatment was well tolerated, erythema rates were similar to outpatient therapy, there were no complaints and the vast majority would choose home over outpatient phototherapy if required in the future. CONCLUSIONS: Hospital supervised home phototherapy appears as safe and effective as outpatient therapy and provides equality of access for patients who cannot attend for outpatient therapy. These patients may otherwise be inadequately treated or given more costly and higher risk systemic therapies, particularly for psoriasis. Commissioners and clinicians involved in dermatology services should provide accessible phototherapy for all patients who might benefit, utilizing home phototherapy where outpatient access is not possible.

Self-administration of hospital-based narrowband ultraviolet B (TL-01) phototherapy: a feasibility study in an outpatient setting.

BACKGROUND: Self-administration of narrowband (TL-01) ultraviolet (UV)B phototherapy by patients at home is a safe and effective mode of treatment. Could selected patients self-administer phototherapy in hospital? OBJECTIVES: To assess the feasibility of outpatient self-administration of UVB phototherapy as a potential service development. METHODS: A total of 20 patients with psoriasis (n = 15) and eczema (n = 5) (13 female, mean age 32 years, range 17-56 years) were included in this pilot project. Patients underwent a training programme over 2 days, which included a minimal erythemal dose test and supervised treatment, prior to commencing self-administration of phototherapy. Questionnaires were used to gather feedback from patients and staff. RESULTS: Treatment data were collected for 18 of the 20 patients. The mean number of exposures was 25 (range 3-45), and the mean cumulative dose was 16 J cm(-2) (range 0·23-41·27 J cm(-2) ). No unexpected adverse effects were noted. These results were similar to those of a sample group of outpatients who had nurse-administered UVB phototherapy, for whom the mean number of exposures was 24 (range 4-49) and the mean cumulative dose was 17 J cm(-2) (range 0·53-71·16 J cm(-2) ). Thirteen patients completed the questionnaires. All concluded that the training programme sufficiently prepared them for self-administering phototherapy, and 12 reported that they would be happy to self-administer treatment in the future. CONCLUSIONS: Self-administration of UVB phototherapy is practicable, safe and effective for most selected patients. This mode of treatment provides training and support for patients to gain more control over management of their skin disease, empowering them to take an active role in their treatment. Self-administration of UVB phototherapy by outpatients provides an intermediate level of care between nurse-administered hospital phototherapy and self-administered home phototherapy.

Using extended reality (XR) for medical training and real-time clinical support during deep space missions.

Medical events can affect space crew health and compromise the success of deep space missions. To successfully manage such events, crew members must be sufficiently prepared to manage certain medical conditions for which they are not technically trained. Extended Reality (XR) can provide an immersive, realistic user experience that, when integrated with augmented clinical tools (ACT), can improve training outcomes and provide real-time guidance during non-routine tasks, diagnostic, and therapeutic procedures. The goal of this study was to develop a framework to guide XR platform development using astronaut medical training and guidance as the domain for illustration. We conducted a mixed-methods study-using video conference meetings (45 subject-matter experts), Delphi panel surveys, and a web-based card sorting application-to develop a standard taxonomy of essential XR capabilities. We augmented this by identifying additional models and taxonomies from related fields. Together, this "taxonomy of taxonomies," and the essential XR capabilities identified, serve as an initial framework to structure the development of XR-based medical training and guidance for use during deep space exploration missions. We provide a schematic approach, illustrated with a use case, for how this framework and materials generated through this study might be employed.

A randomized phase II pharmacokinetic and pharmacodynamic study of indisulam as second-line therapy in patients with advanced non-small cell lung cancer.

PURPOSE: The primary aim of this study was to measure the objective tumor response rate following treatment with indisulam [E7070; N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide] as second-line therapy in patients with advanced non-small cell lung cancer. The secondary aims were to determine progression-free survival, to assess the safety and tolerability of indisulam, and to study its pharmacokinetic and pharmacodynamic profile. EXPERIMENTAL DESIGN: Patients were randomized to receive indisulam every 3 weeks either as a single i.v. dose of 700 mg/m(2) on day one (dx1) or 130 mg/m(2) given on days 1 to 5 inclusive as a daily infusion (dx5). All patients had previously received platinum-based chemotherapy. RESULTS: Forty-four patients were randomized. Only minor responses were seen. Myelosuppression, gastrointestinal symptoms, and lethargy were the most common toxicities and were more frequent in the dx1 arm. The pharmacokinetics of indisulam in each treatment schedule were adequately described using a previously developed population pharmacokinetic model and were mostly consistent with the results of the phase I program. Flow cytometric analysis of endobronchial and metastatic disease revealed a reduction in the fraction of cycling cells and an increase in apoptosis following indisulam compared with pretreatment levels. CONCLUSIONS: We conclude that, despite evidence of tumor-specific indisulam-induced apoptosis, neither of these treatment schedules has single-agent activity as second-line treatment of non-small cell lung cancer.

An unreported complication of acute pancreatitis.

Acute pancreatitis constitutes 3% of all admissions with abdominal pain. There are reports of osteal fat necrosis leading to periosteal reactions and osteolytic lesions following severe pancreatitis, particularly in long bones. A 54-year-old man was admitted to our hospital with acute pancreatitis, who later developed spinal discitis secondary to necrotizing pancreatitis. He was treated conservatively with antibiotics and after a month he recovered completely without any neurological deficit. This case is reported for its unusual and unreported spinal complications after acute pancreatitis.

Undergraduate medical students' perceptions and expectations of theatre-based learning: how can we improve the student learning experience?

OBJECTIVE: Much of the student experience in theatre depends on the interaction between student and surgeon, and having the opportunity to take part in procedures. Theatre-based teaching can be seen as having little inherent benefit otherwise. We wished to identify other factors contributing to the experience of theatre-based teaching. DESIGN: A questionnaire survey, using forced-choice and open questions, of undergraduate medical students with experience of surgical attachments. SETTING AND PARTICIPANTS: 54 final (5th) year medical students, University of Aberdeen. ANALYSIS: Responses on the closed questions are presented as percentages. The themes arising from the open questions were identified and the relationships among these themes explored. RESULTS: Student expectations of learning focused on knowledge acquisition. Students learning experiences varied widely, depending on how welcome they felt in theatre. Visibility and active participation influenced the experience. Students did not feel adequately prepared for getting the most out of this learning experience. CONCLUSIONS: The student experience may be skewed by unrealistic expectations of theatre-based learning. Clear and realistic learning objectives, preparation in terms of familiarity with the environment and staff roles, embedding the experience in the patient's journey/care pathways, faculty expectations being clearly communicated to clinical teaching staff and, perhaps above all, approachability of theatre staff are likely to improve the learning experience.

Teaching surgeons about non-technical skills.

BACKGROUND: Analyses of adverse events in surgery reveal that underlying causes are often behavioural, such as communication failures, rather than technical. Non-technical (i.e. cognitive and interpersonal) skills, whilst recognised, are not explicitly addressed in surgical training. However, surgeons need to demonstrate high levels of these skills, as well as technical proficiency, to maximise safety and quality in the operating theatre. This article describes a prototype training course to raise surgeons' awareness of non-technical skills. METHODS: The course syllabus was based on a new taxonomy of surgeons' non-technical skills (NOTSS) which has four principal categories: situation awareness, decision-making, communication and teamwork, and leadership. Three, one-day training courses were attended by 21 surgeons. RESULTS: All surgeons reported that they found explicit review and discussion of these skills and component behaviours helpful for self-reflection. They rated the content as interesting and relevant and the majority declared their intention to make some changes to their behaviour during surgery. CONCLUSIONS: It was concluded that this type of training could enhance the surgical training portfolio and should be an integral feature of the development and assessment of operative skills.

Non-technical skills for surgeons in the operating room: a review of the literature.

BACKGROUND: This review examines the surgical and psychological literature on surgeons' intraoperative non-technical skills. These are the critical cognitive and interpersonal skills that complement surgeons' technical abilities. The objectives of this paper are (1) to identify the non-technical skills required by surgeons in the operating room and (2) assess the behavioral marker systems that have been developed for rating surgeons' non-technical skills. METHODS: A literature search was conducted against a set of inclusion criteria. Databases searched included BioMed Central, Medline, EDINA BIOSIS, Web-of-Knowledge, PsychLit, and ScienceDirect. RESULTS: A number of "core" categories of non-technical skills were identified from 4 sources of data: questionnaire and interview studies, observational studies, adverse event analyses, and the surgical education/competence assessment literature. The main skill categories were communication, teamwork, leadership, and decision making. The existing frameworks used to measure surgeons' non-technical skills were found to be deficient in terms of either their psychometric properties or suitability for rating the full range of skills in individual surgeons. CONCLUSIONS: Further work is required to develop a valid taxonomy of individual surgeons' non-technical skills for training and feedback.

Attitudes to teamwork and safety in the operating theatre.

BACKGROUND: A survey was undertaken to assess surgical team members' attitudes to safety and teamwork in the operating theatre. METHOD: The Operating Room Management Attitudes Questionnaire (ORMAQ) measures attitudes to leadership, teamwork, stress and fatigue and error. A version of the ORMAQ was distributed to surgical teams in 17 hospitals in Scotland. A total of 352 responses were analysed, 138 from consultant surgeons, 93 from trainee surgeons and 121 from theatre nurses. RESULTS: Respondents generally demonstrated positive attitudes to behaviours associated with effective teamwork and safety. Attitudes indicating a belief in personal invulnerability to stress and fatigue were evident in both nurses and surgeons. Consultant surgeons had more positive views on the quality of surgical leadership and communication in theatre than trainees and theatre nurses. While the ubiquity of human error was well recognised, attitudes to error management strategies (incident reporting, procedural compliance) suggest that they may not be fully functioning across hospitals. While theatre staff placed a clear priority on patient safety against other business objectives (e.g. waiting lists, cost cutting), not all of them felt that this was endorsed by their hospital management. CONCLUSIONS: Attitude surveys can provide useful diagnostic information relating to behaviour and safety in surgical units. Discrepancies were found between the views of consultants compared with trainees and nurses, in relation to leadership and teamwork. While attitudes to safety were generally positive, there were several areas where theatre staff did not seem to appreciate the impact of psychological factors on technical performance.

Pharmacokinetics and metabolism of ifosfamide administered as a continuous infusion in children.

The pharmacokinetics and metabolism of ifosfamide was investigated in a group of 16 pediatric patients (5 girls) aged 1-17 years. Each received a dose of 3 g/m2/day for up to 3 days by continuous infusion. Plasma and urine were collected, and concentrations of ifosfamide and its principal metabolites were determined by a quantitative high-performance thin layer chromatography method. During 3 days of continuous infusion, the plasma concentrations of parent drug decreased. This was accompanied by a continuous increase in dechloroethylated products in plasma but not in urine. Estimated pharmacokinetic parameters (clearance, volume of distribution, and half-life) were dependent on body size and age but not any other patient variable. Renal clearance was a relatively minor route of elimination for parent drug and corresponded to < 25% of glomerular filtration rate. Metabolite data from plasma and urine indicated a high degree of interindividual variation in metabolism. Comparison of metabolite recoveries in urine indicated a positive correlation between activation and inactivation routes of metabolism. Prior exposure to ifosfamide was associated with a higher recovery in urine of dechloroethylated metabolites. The severity of hematological toxicity was inversely correlated with glomerular filtration rate but not to parameters of ifosfamide metabolism. There was marked variation in levels of the carboxy metabolite, which could not be detected in the plasma of 5 subjects. However, evidence for a polymorphism in metabolism to this metabolite was weaker than that seen with the isomeric oxazaphosphorine cyclophosphamide. There appeared to be a higher clearance of ifosfamide in pediatric patients compared to adults. The significance of this, and of the variation in metabolism of ifosfamide, for clinical outcome remains to be established, but the increase in the dechloroethylation route of metabolism may be associated with an increased risk of toxicity.

Cyclophosphamide metabolism in children.

The alkylating agent cyclophosphamide is a prodrug which is metabolized in vivo to produce both therapeutic and toxic effects. Cyclophosphamide metabolism was investigated in 36 children with various malignancies. Concentrations of cyclophosphamide and its principal metabolites were measured in plasma and urine using a quantitative high-performance TLC method. The results indicated a high degree of inter-patient variation in metabolism. In contrast to previous adult studies on urinary metabolites, plasma carboxyphosphamide concentrations did not support the existence of polymorphic metabolism. Plasma concentrations of dechlorethylcyclophosphamide and carboxyphosphamide were correlated in individual patients, suggesting that the activity of both aldehyde dehydrogenase and cytochrome P450 enzyme(s) determine carboxyphosphamide production in vivo. The presence of ketocyclophosphamide in plasma was strongly associated with dexamethasone pretreatment and was also accompanied by a high clearance of the parent drug. Interpatient differences in metabolism reflect individual levels of enzyme expression and may contribute to variation in clinical effect.

High-dose cyclophosphamide for poor-prognosis and recurrent pediatric brain tumors: a dose-escalation study.

PURPOSE: To determine the maximum-tolerated dose (MTD) of cyclophosphamide (CTX) when administered over 2 consecutive days followed by hematopoetic stem-cell rescue given as two sequential courses to children with glioblastoma multiforme, poor-prognosis pontine gliomas, and other recurrent CNS tumors. PATIENTS AND METHODS: Two identical doses of CTX were administered 24 hours apart to 14 children and followed by hematopoetic stem-cell rescue. This treatment was repeated immediately following hematologic recovery. The starting dose of CTX was 2.5 g/m2/d with increments of 0.5 g/m2/d. CTX pharmacokinetics and metabolism were measured during 22 courses of treatment. Toxicity and tumor response were recorded. RESULTS: There were two toxic deaths at the dose level of 4 g/m2/d. These were not clearly related to cardiac toxicity and may have been due to generalized capillary leak syndrome. Thus, the MTD of CTX was 3.5 g/m2/ d. There were six complete responses (CRs) (46%; (95% confidence interval [CI], 19% to 73%) and four partial responses (PRs) (31%; 95% CI, 6% to 56%), and one patient achieved stable disease. All children with intracranial primitive neuroectodermal tumors (PNETs) improved following CTX. The median duration of tumor response was 6 months (range, 4 to 29) and only one patient remains disease-free following CTX alone. Overall survival is 21% (95% CI, 13% to 29%) at a median follow-up time of 27 months (range, 12 to 34). CONCLUSION: The MTD of CTX when followed by hematopoetic stem-cell rescue is 3.5 g/m2 administered on each of 2 consecutive days. This treatment was tolerable in children with poor-prognosis brain tumors and produced complete responses in children with recurrent PNETs.

Cyclophosphamide and ifosfamide metabolites in the cerebrospinal fluid of children.

Although both cyclophosphamide (CP) and ifosfamide (IF) are used in the treatment of central nervous system tumors, little is known about the concentration of either drug or their metabolites in the cerebrospinal fluid (CSF) of children. The concentrations of the parent oxazaphosphorine and its principal metabolites were measured simultaneously in the plasma and CSF of 25 children. Twenty-one patients received CP for the treatment of either acute lymphoblastic leukemia, non-Hodgkin's lymphoma, or medulloblastoma, and 4 children received IF for the treatment of rhabdomyosarcoma. A high degree of interpatient variation was seen in terms of the CSF concentration of CP and the CSF:plasma ratio. The CSF:plasma ratio was greater for IF than for CP (P < 0.001). In contrast to IF, where the majority of metabolites was measured in the CSF, no child receiving CP had detectable metabolites. Children receiving dexamethasone had lower concentrations of CP in the CSF (P = 0.04). The CSF:plasma ratio for isophosphoramide mustard was greater than that for either parent drug or any other metabolite. These results demonstrate that IF enters the CSF to a greater extent than CP in children. The ability of both IF and CP and their metabolites to cross the blood-brain barrier may be reduced by dexamethasone.

Cyclophosphamide metabolism in children with non-Hodgkin's lymphoma.

PURPOSE: The purpose of our study was to determine whether variation in cyclophosphamide metabolism influences the incidence of recurrence among children receiving chemotherapy for B-cell non-Hodgkin's lymphoma. EXPERIMENTAL DESIGN: The pharmacokinetics and metabolism of cyclophosphamide were studied during a single course of treatment in 36 children receiving a uniform chemotherapy regimen for B-cell non-Hodgkin's lymphoma and were analyzed in terms of disease recurrence and hematological toxicity. RESULTS: At a median follow-up of 43 months (range, 17-98 months), six children had developed recurrent disease, giving an overall disease-free survival of 83%. The median clearance of cyclophosphamide in patients who remain free of B-cell non-Hodgkin's lymphoma was 3.7 liter/h/m(2) (range, 2.3-5.0 liter/h/m(2)), compared with 2.2 (range, 1.5-2.5 liter/h/m(2)) in those with disease recurrence. Likelihood of recurrence was higher in patients with low clearance (<3.5 liter/h/m(2)) of cyclophosphamide (P < 0.01) and positively related to detection of the inactive metabolites carboxyphosphamide and dechloroethylcyclophosphamide in plasma (P = 0.01). There was no correlation between cyclophosphamide metabolism and hematological toxicity. CONCLUSIONS: Inadequate clearance of cyclophosphamide to active metabolites is associated with increased risk of recurrence of B-cell non-Hodgkin's lymphoma in children. Modified chemotherapy strategies should be considered in patients who exhibit low rates of clearance of the parent drug and/or extensive production of inactive metabolites.