Administration Of Intrathecal Chemotherapy Research Articles

Lumbar spinal fluid collections in children treated with intrathecal chemotherapy: Elevated CSF protein as a diagnostic clue

Subdural fluid collections can interfere with the effective intrathecal administration of chemotherapy by lumbar puncture (LP). We detected this complication in six children who were treated for acute lymphoblastic leukemia (ALL) and presented with an elevated protein concentration of the cerebrospinal fluid (CSF) during routine LP. Contrary to expectation the lumbar fluid collections persisted in two cases and in one case required the insertion of an Ommaya reservoir to continue intrathecal chemotherapy. Awareness and detection of this complication by imaging is important because of its potential to interfere with effective CNS-directed chemotherapy of ALL.

Catheter Placement for Ommaya Reservoirs with Frameless Surgical Navigation: Technical Note

Objective: Infusion of intraventricular chemotherapy requires precise ventricular catheter placement in oncology patients to avoid intraparenchymal infusion. We assessed the safety and precision of using frameless surgical navigation for the placement of Ommaya reservoir catheters. Methods: In 20 consecutive patients who required Ommaya reservoirs for the administration of intrathecal chemotherapy, the catheters were positioned with the guidance of frameless stereotaxy. Precision of catheter placement, operative time, operative complications, and postoperative complications were assessed. Results: All catheters were completely within cerebrospinal fluid and 90% were within 5 mm of the intended target, the ipsilateral foramen of Monro. The average operative time was 47 min, and there were no intraoperative complications. There were no reports of leukoencephalopathy, and 3 patients had minor delayed complications. Conclusion: Frameless surgical navigation is a useful and efficient method for ensuring accurate catheter placement during Ommaya reservoir implantation, and it reduces the risk of potential parenchymal toxicity.

Platelet count has no influence on traumatic and bloody lumbar puncture in children undergoing intrathecal chemotherapy

British Committee for Standards in Haematology, Blood Transfusion Task Force (2003) produced guidelines suggesting a platelet count of ≥50 × 109/l to safely proceed with lumbar puncture (LP). This has led us to review our institute's policy of a platelet count of ≥30 × 109/l as a safety cutoff for LP procedures and administration of intrathecal chemotherapy. There is obvious concern because a low platelet count may be associated with devastating neurological complications due to spinal bleeding. Furthermore, on presentation if a traumatic tap occurs, leukaemic cells circulating in the blood may be introduced into the cerebrospinal fluid (CSF), thereby possibly worsening the patient's prognosis (Gajjar et al, 2000). Howard et al (2000) reported a large retrospective analysis of 4309 LPs performed in 959 children, including 941 procedures with platelet count of <50 × 109/l with no neurological haemorrhagic complications. This article recommended that a platelet count of 10 × 109/l or higher would be adequate to perform routine LP. The authors (Howard et al, 2002), found that platelet counts of below 100 × 109/l were associated with increased risk of traumatic or bloody tap, but this risk was not different across platelet categories once the platelet count reduced below this threshold. Our aim in this retrospective cohort study was to review the available literature, ensure the safety of our practice and determine if the platelet count had any influence on the rate of traumatic LP performed. We report a review of 54 consecutive paediatric patients, 29 male and 25 female, age range 3 months to 17 years (median 7 years), with haematological malignancy who underwent a total of 738 LP procedures at Royal Manchester Children's Hospital between March 2001 and June 2005. All patients underwent LP and intrathecal chemotherapy under general anaesthetic conditions and procedures were performed by experienced clinicians (Consultant or Specialist registrar) according to the national guidelines. Patients underwent between 1 and 25 (median 11) procedures LPs from diagnosis. For each LP, the platelet count and number of red blood cells (RBCs) within CSF was recorded. Traumatic LP was defined as an LP in which cerebral fluid contained at least 10 RBCs/μl and bloody LP which the CSF contained at least 500 RBCs/μl. Of the 738 LPs performed, 65 (9%) were traumatic and 30 (4%) were bloody. No bleeding or neurological complications observed in any of the patients. Regression curve analysis showed no correlation with platelet count and red cell count in the CSF (R2 = 0.004). There appeared to be no increase in the incidence of traumatic or bloody taps in patients with a lower pre-procedure platelet count (Fig 1). Incidence of traumatic and bloody taps dependant on platelet count (×109/l). Within this cohort of patients with platelet count <50 × 109/l we observed no bleeding complications, and no increase in traumatic or bloody CSF. These findings support previous published data. These results indicate a significantly less traumatic rate than previously reported (Howard et al, 2000). At our institute we attribute the low rate of red cell contamination to experienced clinicians, dedicated general anaesthetic lists, and specific LP 24-guage needles. This study and existing evidence in the literature would support the safety of performing LPs with platelet counts ≥30 × 109/l. This policy enabled 27 of 738 patients (3.6%) to avoid a platelet transfusion, and thus reduced donor exposure, platelet-associated infections, delay in procedure, as well as reducing costs and making better use of platelet resources.

Syndrome of inappropriate secretion of ADH after administration of intrathecal chemotherapy in acute promyelocytic leukemia with empty sella of pituitary gland

Dear Editor, A 66-year-old woman who had developed acute promyelocytic leukemia was admitted with bicytopenia and administered all-trans-retinoic acid (45 mg/m), idarubicin (12 mg/m for 3 days), and cytarabine (Ara C 100 mg/m for 5 days). She first obtained remission 40 days after the administration of induction therapy. Then she was administered two courses of consolidation therapy (first course: Ara C 200 mg/m for 5 days and mitoxantrone 7 mg/m for 3 days; second course: Ara C 150 mg/m for 5 days and daunorubicin 40 mg/m for 3 days), resulting in complete remission. Before the third course, she was administered intrathecal chemotherapy [IT; methotrexate (MTX) 15 mg, Ara C 40 mg, prednisolone (PSL) 10 mg]. Chemotherapy was performed after the administration of IT. She daily ingested almost 2,500 ml of liquid, which contained an infusion of drip, and her urine totaled from 1,600 to 3,700 ml (average of 2,600 ml). She developed hyponatremia after the administration of IT. On the 5th day of IT, the patient developed general fatigue followed by a gradual disturbance of consciousness. As indicated in Fig. 1, her serum sodium level had fallen to 109 mEq/l (normal range 135 to 147 mEq/l), and plasma osmolarity was 229.5 mOsm/kg H2O (normal range 280 to 300 mOsm/kg H2O) without edema. After treatment with hypertonic saline infusion and minocycline hydrochloride (MINO), she gradually regained consciousness. On the 7th day of IT, her serum sodium level had recovered to 130 mEq/l. Plasma osmolarity was still 277 mOsm/kg H2O, urine osmolarity was 578 mOsm/kg H2O (normal range 500 to 800 mOsm/kg H2O), and her ADH level was 1.0 pg/ml (normal range 0.3 to 3.5 pg/ml). Magnetic resonance imaging (MRI) of the pituitary gland showed only neurohypophysis (lobus posterior) (Fig. 2). Her symptoms and abnormal laboratory data completely disappeared 1 month after the IT. Inappropriate secretion of ADH (SIADH) is characterized by water retention, hyponatremia, and central nervous system symptoms. SIADH can be induced by various causes, including central nervous disorders, endocrine diseases, paraneoplastic syndromes, and anticancer agents such as vincristine and cyclophosphamide [1–4]. On the other hand, MTX and PSL have not been reported to be the causative agents of SIADH. Just a single investigator reported that one of thirteen patients with a high dosage of intravenous Ara C (3–7.5 g/m) developed SIADH, but not in a patient with IT [5]. This case lacked any viral infection or disease recurrence, and the administration of IT was only evident after the development of SIADH. One reason the patient developed SIADH is thought to reflect the Ann Hematol (2007) 86:149–150 DOI 10.1007/s00277-006-0199-9

New Agents for Intrathecal Administration

Intrathecal administration of chemotherapy, with or without radiation therapy, is the primary treatment modality for the prevention and treatment of central nervous system (CNS) metastases in patients with leukemia or lymphoma. Although this treatment strategy has been very effective for patients with hematological malignancies, currently available intrathecal agents are relatively ineffective for patients with neoplastic meningitis resulting from an underlying solid or CNS tumor effective. This article provides an overview of some of the practical considerations and limitations associated with intrathecal chemotherapy, and is followed by a comprehensive review of some of the preclinical and early phase clinical trials of novel anticancer agents and treatment strategies using the intrathecal route.

PII: S0090-3019(05)00196-5

Ommaya reservoirs are used for administration of intrathecal chemotherapy and cerebrospinal fluid sampling. Ventricular catheter placement for these purposes requires a high degree of accuracy. Various options exist to optimize catheter placement. We analyze a cohort of patients receiving catheters using 2 different technologies.Retrospective chart review was performed on patients undergoing Ommaya reservoir placement between 2011 and 2014. Most procedures were assisted by either frameless stereotactic neuronavigation or fluoroscopic guidance with pneumoencephalogram. Catheter accuracy, revision rates, perioperative complications, and operative time were measured. Preoperative similarities and differences in diagnosis, demographics, and ventricular size were also recorded to avoid a biased assessment of our results.One-hundred and forty-five patients were included, 57 using fluoroscopic guidance and 88 using frameless stereotaxy. Common diagnoses in both groups were lymphoma and leptomeningeal disease. Qualitative measures of catheter placement accuracy showed no significant difference between the 2 groups. Proximity to the foramen of Monro favored fluoroscopy by a small margin (8.6 mm vs. 10.2 mm, P = 0.03). Overall revision rates were not significantly different between the groups (3.5% vs. 4.5%, P = 1.00). Early surgical complications occurred in 6.8% of the frameless stereotaxy group and 1.8% of the fluoroscopy group (P = 0.25).Ommaya reservoirs can be placed accurately using different methods. Although there are slight differences between fluoroscopy and frameless stereotaxy in quantitative accuracy and procedure time, there is no significant advantage of 1 method over the other when evaluating revision or complication rates. Technique familiarity and surgeon preference may dictate the preferred procedure.

Important Role of Routine Cerebrospinal Fluid Examination in Diagnosing Central Nervous System Relapse during Maintenance Therapy in Pediatric Acute Lymphoblastic Leukemia.

Despite the success of central nervous system (CNS) preventive therapy in reducing the incidence of CNS recurrence in pediatric acute lymphoblastic leukemia (ALL) on therapy, CNS relapse continues to be a significant cause of treatment failure and is observed in 5–10% of patients. While most pediatric ALL treatment protocols mandate periodic lumbar puncture (LP) surveillance for the length of therapy, some centers have stopped collecting routine CSF samples unless there are suggestive signs or symptoms of CNS involvement. Our objective herein was to assess the value of routine cerebrospinal fluid (CSF) obtained while performing routine LPs for administration of intrathecal chemotherapy in diagnosing CNS relapse in children with ALL in the maintenance phase.Patients and Methods: All children (0–18 years) with ALL, diagnosed and treated at the Hospital for Sick Children, Toronto, Canada between 1994–2004 were subjected to a retrospective analysis. Original reports for CNS relapse during maintenance therapy were examined to determine whether CNS relapse was diagnosed based on routine CSF sample obtained while administering intrathecal chemotherpy or a CSF sample obtained based on signs and symptoms or after a diagnosis of a bone marrow relapse.Results: Four hundred and ninety four children were diagnosed and treated in our institution during the study period. Children were treated based on the children oncology group (COG), pediatric oncology group (POG) and local protocols where applicable. Thirty-one children (6.3%) suffered CNS relapse while on maintenance therapy. Twenty-one had an isolated CNS relapse and ten had a combined bone marrow and CNS relapse. Seventy-six percent (16/21) isolated CNS relapses were diagnosed base on routine CSF samples obtained from asymptomatic children while administering intratheacal chemotherapy. Conversely, all patients with combined bone marrow and CNS relapse presented with symptoms and signs that warranted CSF examination.Conclusion: Routine CSF examinations are important in detecting CNS relapse in children with ALL during maintenance therapy. Furthermore, routine CSF sampling may detect isolated CNS relapse in asymptomatic children with ALL prior to extension into combined relapse where prognosis is less favorable.

Myelopathy Due to Intrathecal Chemotherapy

Intrathecal chemotherapy and systemic chemotherapy are used for both prophylaxis and treatment of central nervous system disease in hematologic malignancies. However, intrathecal treatment has some adverse effects, such as arachnoiditis, progressive myelopathy, and leukoencephalopathy. The authors describe six children in whom myelopathy and adhesive arachnoiditis developed after administration of intrathecal chemotherapy including methotrexate, cytosine arabinoside, and prednisolone. Urinary retention and incontinence, the main presenting complaints in all patients, developed within 12 hours after intrathecal therapy and spontaneously resolved within 7 days. Two patients were unable to walk. In these two, weakness in the lower extremities gradually recovered by 1 month but urinary incontinence did not improve. None of the children had sensory loss. On follow-up periodic recurrent urinary tract infection was noted in four patients. MRI findings corresponded to arachnoiditis. No response was recorded on tibial nerve somatosensory evoked potentials in all patients. Intrathecal chemotherapy, especially methotrexate, can cause spinal cord dysfunction in children with acute lymphoblastic leukemia and non-Hodgkin's lymphoma. Arachnoiditis should be kept in mind as a causative factor in recurrent urinary tract infection in patients receiving intrathecal chemotherapy.

Propofol sedation by emergency physicians for elective pediatric outpatient procedures

Study objective We describe the efficacy of propofol sedation administered by pediatric emergency physicians to facilitate painful outpatient procedures. Methods By using a protocol for patients receiving propofol sedation in an emergency department–affiliated short-stay unit, a prospective, consecutive case series was performed from January to September 2000. Patients were prescheduled, underwent a medical evaluation, and met fasting requirements. A sedation team was present throughout the procedure. All patients received supplemental oxygen. Sedation depth and vital signs were monitored while propofol was manually titrated to the desired level of sedation. Results There were 291 separate sedation events in 87 patients. No patient had more than 1 sedation event per day. Median patient age was 6 years; 57% were male patients and 72% were oncology patients. Many children required more than 1 procedure per encounter. Most commonly performed procedures included lumbar puncture (43%), intrathecal chemotherapy administration (31%), bone marrow aspiration (19%), and bone biopsy (3%). Median total propofol dose was 3.5 mg/kg. Median systolic and diastolic blood pressures were lowered 22 mm Hg (range 0 to 65 mm Hg) and 21 mm Hg (range 0 to 62 mm Hg), respectively. Partial airway obstruction requiring brief jaw-thrust maneuver was noted for 4% of patient sedations, whereas transient apnea requiring bag-valve-mask ventilation occurred in 1% of patient sedations. All procedures were successfully completed. Median procedure duration was 13 minutes, median sedation duration was 22 minutes, and median total time in the short stay unit was 40 minutes. Conclusion Propofol sedation administered by emergency physicians safely facilitated short painful procedures in children under conditions studied, with rapid recovery.

WT1 mRNA in cerebrospinal fluid associated with relapse in pediatric lymphoblastic leukemia.

The goal was to assess a possible relationship between the detection of mRNA from WT1 gene in cerebrospinal fluid (CSF) and neoplastic relapse in pediatric patients being treated for lymphoid precursor cell neoplasms. Ninety-four patients less than 19 years old with lymphoid precursor cell leukemia in hematologic remission and without central nervous system (CNS) compromise were included. Cytology, cytochemistry, cell count, and qualitative RT-PCR were performed using routine CSF samples obtained during intrathecal chemotherapy administration. The main outcome measure was clinical, radiologic, and cytologic evidence of CNS, hematologic or any other type of neoplastic relapse. At some time during follow-up, 28.7% of the patients had a positive WT1 CSF test. Relapses included 10 patients with isolated hematologic, 4 with isolated CNS, 1 with combined CNS and hematologic, and 1 with mediastinal relapse; the maximal follow-up period was 312 days. A statistically significant association was found between the detection of WT1 in CSF and CNS relapse. Adjusted hazard rate ratios of 5.04 (95% confidence interval 1.33-19.12) and 7.48 (2.34-23.93) were estimated for isolated hematologic relapse and for all types of relapses, respectively. Although it is likely that the short follow-up period underestimated the incidence of relapse, this study was able to identify a strong association between WT1 mRNA detection and CNS or hematologic relapse. These findings represent a potentially novel and useful approach for subclinical disease detection.

Intrathecal Administration of Chemotherapy in Children with Brain Tumors: Effects on Cerebral Hemodynamics

Intrathecal Administration of Chemotherapy in Children with Brain Tumors: Effects on Cerebral Hemodynamics

Propofol anesthesia for invasive procedures in ambulatory and hospitalized children: experience in the pediatric intensive care unit.

To describe our experience with propofol anesthesia to facilitate invasive procedures for ambulatory and hospitalized children in the pediatric intensive care unit (PICU) setting. We retrospectively reviewed the hospital records of 115 children who underwent 251 invasive procedures with propofol anesthesia in our multidisciplinary, university-affiliated PICU during a 20-month period. All patients underwent a medical evaluation and were required to fast before anesthesia. Continuous monitoring of the patient's cardiorespiratory and neurologic status was performed by a pediatric intensivist, who also administered propofol in intermittent boluses to obtain the desired level of anesthesia, and by a PICU nurse, who provided written documentation. Data on patient demographics, procedures performed, doses of propofol used, the occurrence of side effects, induction time, recovery time, and length of stay in the PICU were obtained. Propofol anesthesia was performed successfully in all children (mean age, 6.4 years; range, 10 days to 20.8 years) who had a variety of underlying medical conditions, including oncologic, infectious, neurologic, cardiac, and gastrointestinal disorders. Procedures performed included lumbar puncture with intrathecal chemotherapy administration, bone marrow aspiration and biopsy, central venous catheter placement, endoscopy, and transesophageal echocardiogram. The mean dose of propofol used for induction of anesthesia was 1.8 mg/kg, and the total mean dose of propofol used was 8.8 mg/kg. In 13% of cases, midazolam also was administered but did not affect the doses of propofol used. The mean anesthesia induction time was 3.9 minutes, and the mean recovery time from anesthesia was 28.8 minutes for all patients. The mean PICU stay for ambulatory and ward patients was 140 minutes. Hypotension occurred in 50% of cases, with a mean decrease in systolic blood pressure of 25%. The development of hypotension was not associated with propofol doses, the concomitant use of midazolam, or the duration of anesthesia, but was associated with older patient age. Hypotension was transient and not associated with altered perfusion. Intravenous fluid was administered in 61% of the cases in which hypotension was present. Respiratory depression requiring transient bag-valve-mask ventilation occurred in 6% of cases and was not associated with patient age, propofol doses, concomitant use of midazolam, or the duration of anesthesia. Transient myoclonus was observed in 3.6% of cases. Ninety-eight percent of procedures were completed successfully, and no procedure failures were considered secondary to the anesthesia. Patients, parents, and health care providers were satisfied with the results of propofol anesthesia. Propofol anesthesia can safely facilitate a variety of invasive procedures in ambulatory and hospitalized children when performed in the PICU and is associated with short induction and recovery times and PICU length of stay. Hypotension, although usually transient, is common, and respiratory depression necessitating assisted ventilation may occur. Therefore, appropriate monitoring and cardiorespiratory support capabilities are essential. Propofol anesthesia in the PICU setting is a reasonable therapeutic option available to pediatric intensivists to help facilitate invasive procedures in ambulatory and hospitalized children.

Blood to cerebrospinal fluid human chorionic gonadotropin-beta ratios in intracranial germ cell tumors

Levels of human chorionic gonadotropin-beta (HCG-beta) are elevated in up to 43% of patients with intracranial germ cell tumors (GCTs) and are useful in the diagnosis of these tumors and the follow up of such patients. The ratio of blood HCG-beta to lumbar cerebrospinal fluid (CSF) HCG-beta in these patients at presentation has not been defined. Twenty-two patients with intracranial GCTs have been treated at St. Bartholomew's Hospital over the past 15 years. Two (17%) of 12 germinomas and seven (70%) of 10 nongerminomatous GCTs had elevated blood HCG-beta at presentation. Four cases of pineal region GCTs (one of 12 germinomas and three of 10 nongerminomatous GCTs) had paired, elevated, blood and lumbar CSF HCG-beta levels. The mean blood to CSF ratio was 1:10 (range 1.7-18.4), which is substantially lower than the ratio of 286:1 reported in systemic GCTs. The authors confirm the finding of a previous single report showing that ventricular CSF HCG-beta sampling via an accessible ventriculoperitoneal shunt reservoir may give a spuriously negative result, and they discuss the pathophysiology of the blood-brain barrier in the pineal region and the implications of the intrathecal administration of chemotherapy.

Pharmacologic strategies for the treatment of meningeal malignancy.

There have been significant strides in the treatment and prevention of meningeal cancer, particularly meningeal leukemia, during the past thirty years. These advantages are a direct result of innovative therapeutic approaches specifically designed to overcome the limitations of systemically administered chemotherapy. Such approaches include the administration of intrathecal chemotherapy by intralumbar or intraventricular injection, the administration of very high-dose systemic chemotherapy, and the administration of cranial or craniospinal irradiation. A better understanding of the central nervous system pharmacokinetics of commonly used anticancer agents has also resulted in improvements in the treatment of meningeal cancer. In this article, the clinical pharmacology of the most commonly used intrathecal agents and pharmacologic strategies for the treatment of meningeal cancer will be discussed. In addition, an overview of new agents for intrathecal administration and other novel CNS targeted therapies will be presented.

Epidemic iatrogenic Acinetobacter spp. meningitis following administration of intrathecal methotrexate

We report the first outbreak of Acinetobacter species meningitis in a group of children with acute leukaemia following the administration of intrathecal chemotherapy. Eight of twenty patients receiving methotrexate injections on a single day developed signs and symptoms of meningitis within 18 h of treatment, and cases were clustered by time of administration. A cohort study comparing case and non-case patients did not identify any specific host factor associated with meningitis. Acinetobacter calcoaceticus var anitratus was isolated from the cerebrospinal fluid (CSF) of five patients; three patients died. Our investigation determined that the methotrexate was extrinsically contaminated by reused needles, used for reconstitution and administration, which had been inadequately sterilized. Acinetobacter calcoaceticus var anitratus was isolated from an autoclaved needle and a vial of methotrexate used for chemotherapy; these and the clinical isolates had similar antibiograms. After introduction of single-use disposable needles no subsequent cases occurred.