Advances in the treatment of hematological and solid tumor malignancies have impacted positively on overall disease-free survival. Unfortunately, this improvement has resulted in an increase in the incidence of disease recurrence in the leptomeninges.1 Central nervous system (CNS) involvement can occur at initial diagnosis, but more commonly, it is the site of relapse, either solely or as part of systemic relapse.2 The highest frequency of CNS involvement occurs in acute lymphoblastic leukemia (ALL), Burkitt lymphoma/leukemia, and lymphoblastic lymphoma.2–4 Neoplastic meningitis, the leptomeningeal dissemination of metastatic tumors, occurs in approximately 5% of all cancer patients.5 Disease is clinically detectable in 5% to 15% of patients with leukemia and lymphoma and in 5% to 8% of patients with solid tumors (mainly breast and lung carcinomas and melanoma).6
It is recognized that the CNS is a unique “sanctuary” site for malignant disease because it is essentially protected from the effects of systemically administered antineoplastic chemotherapy. Several therapeutic strategies have been used to target neoplastic cells present or potentially existing in the CNS: cranial or cranospinal irradiation, high-dose systemic chemotherapy, and intrathecal (IT) chemotherapy.1,2 Drug concentrations within the CNS depend on a number of factors, including the permeability of the blood-brain barrier to the chemotherapeutic agent, the extent to which the drug is actively transported out of the brain, and the drug volume of distribution in the brain parenchyma.2,7 Methotrexate is the most commonly used systemic medication used in CNS prophylaxis and treatment, but high intravenous (IV) doses must be administered to achieve therapeutic drug concentrations in the tumor and surrounding brain.7
The goal of IT chemotherapy is to maximize CNS drug exposure in the cerebrospinal fluid (CSF) while reducing the potential for systemic drug toxicity.1 The volume of distribution of CSF is much smaller than that of plasma; therefore, a much higher drug concentration can be achieved in CSF using a much smaller dose. The terminal half-life of most drugs is longer in the CSF than in plasma, thus providing prolonged CSF drug exposure, which is critical for cell-cycle–specific agents such as methotrexate and cytarabine.1 Methotrexate, cytarabine, and corticosteroids are the most common medications delivered by the IT route in adults and children.2,8 Practically all prophylactic regimens for leukemia and lymphomas contain methotrexate, either as a single agent or in combination with other agents, typically cytarabine. Corticosteroids, most commonly hydrocortisone, are used to increase cytotoxicity, particularly in ALL, and to reduce the risk of chemical arachnoiditis that may arise in response to other IT medications, especially cytarabine.2 Direct injections of antineoplastic agents into the CSF may cause potential neurological toxicity related to both the procedure itself and the physicochemical properties of the drug.8 Neurotoxicity reported after IT chemotherapy includes acute chemical arachnoiditis, seizures, spinal cord lesions, and encephalopathy.2,8 Care must be taken to use preservative-free medications during IT administration because there are potential risks of anaphylaxis and neurotoxicity from the preservative agent.9
To ensure optimal disease control, IT chemotherapy is commonly given in conjunction with standard chemotherapy protocols, thus providing the opportunity for medication errors. Because of the narrow therapeutic index and high toxicity of antineoplastic agents, the consequences of mistakes in chemotherapy administration are potentially catastrophic. Numerous errors in patients receiving IT chemotherapy have been described in the literature. These have occurred in both adults and children and have led to significant morbidity and mortality. Unfortunately, the incidence of medication errors in this setting is greatly underestimated because many cases go unrecognized or unreported.
Systemic Review Search Strategy
The literature search included published articles limited to the English language and humans in the electronic databases Medline and Embase. Medline/PubMed (1960–June 2013) was searched using the terms antineoplastic agents, methotrexate, vincristine, medication errors, and injections, spinal. Embase (1964–June 2013) was searched using the terms antineoplastic agent, methotrexate, vincristine, medication error, and intraspinal drug administration. References of all relevant articles were reviewed for additional citations. All identified articles describing medication errors associated with the administration of IT chemotherapy in relation to drug overdose or accidental IT administration of antineoplastic agents were evaluated for inclusion in the review.
Overdose of IT methotrexate was first reported in 1967 when a 4-year-old girl with ALL received 10 times the usual dose.10 Since then, a further 21 cases have been reported in the literature (Table 1).11–23 In cases when the reason for the mistake was discussed, most errors have been caused by doses being prepared from a concentrated solution of methotrexate rather than the standard solution11,14–16,18,22,24 or when an intended IV dose prepared in a syringe was inadvertently administered intrathecally.13,24 Strategies for the prevention of this error must be instituted and could include prohibiting the use of concentrated methotrexate solutions in the preparation of IT doses and not preparing IV doses of methotrexate in a syringe but using an small-volume infusion bag instead. These should be used in conjunction with other strategies discussed later in this article.
In most cases, no residual neurotoxicity occurred. Initial symptoms varied, with no neurological effects seen in some patients,10,12,15,20,22 whereas seizures were reported in others.13,16–21 The extent of toxicity was generally related to the dose of methotrexate administered intrathecally. Six patients received doses in excess of 600 mg,13,14,16,20 with 1 of these being 1200 mg.21 A 9-year-old boy was given 54 times the standard dose of IT methotrexate (650 vs 12 mg).13 The error was recognized approximately 45 minutes later and treatment was instigated with CSF exchange, IV folinic acid and dexamethasone, and supportive care. Despite CSF exchange, which removed 78% of the administered methotrexate dose, CSF and serum methotrexate levels were 50- to 100-fold higher than seen following standard therapy. Unfortunately, he sustained an immediate necrotizing leukoencephalopathy, which proved to be fatal 1 month later. Instead of the prescribed dose of 12 mg, an 11-year-old boy received an overdose of 20 mg IT methotrexate.17 Cerebrospinal fluid was withdrawn and IT folinic acid 50 mg was administered, followed by IV folinic acid 100 mg every 4 hours. During the next 24 hours, he received 2 further doses of IT folinic acid 50 mg. He deteriorated over the next 4 days, with worsening renal, hepatic, and pulmonary function. A computed tomographic scan on day 5 showed diffuse cerebral edema, herniation of the cerebellar tonsils, and obliteration of the ventricles. He was declared brain dead and removed from all life support. A subsequent judicial inquiry concluded that IT folinic acid was a major contributor to the death.
Standard treatment in patients who experience overdoses of IT methotrexate includes lumbar puncture to remove methotrexate from the CSF by drainage, ventricular catheter placement and ventriculolumbar perfusion (if feasible) to remove methotrexate by CSF exchange in cases of continued or worsening neurotoxicity, IV administration of folinic acid to prevent systemic methotrexate toxicity, and IV administration of dexamethasone to minimize methotrexate-induced chemical arachnoiditis.20 Carboxypeptidase G2 (CPDG2) is a bacterial enzyme that hydrolyzes methotrexate to its inactive metabolites, 4-deoxy-4-amino-N 10-methylpteroic acid and glutamate.20 Widemann et al20 enrolled patients who received accidental IT methotrexate overdoses into a multi-institutional clinical trial or on a compassionate-use protocol. Seven patients were treated, 4 of whom had CSF exchange before CPDG2 administration intrathecally. After administration, methotrexate concentrations in the CSF declined by more than 98%, some of which may be explained by the CSF exchange, and all patients recovered, except for 2 who experienced short-term memory impairment. In another case, CPDG2 has also been used successfully.23 If available, CPDG2 appears to be a well-tolerated, efficacious adjunct to the management of IT methotrexate overdose.
One case where a 4-year-old boy was administered an intended IV dose of cytarabine 200 mg intrathecally has been reported in the literature.25 Exchange of CSF was performed and no neurotoxicity was seen initially. One month after the incident, unsteady gait and a mild intention tremor in the hands were noted.
Inadvertent IT Administration
There have been numerous reports of antineoplastic agents intended for administration by the parenteral route being inadvertently administered intrathecally. This had led to profound toxicity and, commonly, particularly in the case of vinca alkaloids, death. Despite the introduction of wide-ranging preventative strategies, errors still continue to occur.
The administration of vincristine directly into the CSF has been associated with catastrophic neurotoxicity since it was first reported in 1968.26 A young child was erroneously given vincristine intrathecally and, despite early recognition and CSF exchange, died 3 days later. Numerous cases have since been documented in the literature (Table 2), and it is believed that many more have gone unrecorded.27–55 Information, albeit scant in many cases, is available on 32 reported instances of inadvertent IT administration of vincristine, with 25 resulting in death. The outcome has proven fatal even when the error has been recognized during the actual administration process and only a fraction of the drug was given intrathecally.33 Vincristine inhibits tumor growth principally via interference with mitotic spindle function by binding to tubulin to block its polymerization into microtubules, thereby inhibiting mitosis in metaphase.56 Neurotoxicity results from a subsequent blockage of axonal transport and, thus, in axonal degeneration. Binding to tubulin has been shown to occur in less than 5 minutes, so any intervention, however rapid, has a limited chance of success.57
After vincristine administration into the CSF, length of survival varied from 3 to 83 days (see Table 2). Of the 7 nonlethal cases, 2 died of their primary disease32,34 and 5 were alive at last report.36,38,41,47,51 Detailed descriptions of findings are available from the individual case reports in which autopsies were performed.26,28,29,31,33,37,41,43,44,46 The principal damage was generally seen in the brain stem, cerebellum, and spinal cord, with severity greater in the neurons bordering the CSF. Fatalities appeared due to a progressive ascending myeloencephalopathy.
In most cases, reasons as to why the error happened were not investigated. Where this was explored, multiple causes were often identified. These included mistaking vincristine for the intended IT medication,27,29,30,39,44,50 mislabeling of syringes,31 IV and IT drugs brought into the treatment area at the same time,34,35,39,42,49,50 inexperienced medical staff administering medication,37,42,45 patients not treated in a specialty unit,39,42,49 treatment given outside normal hours,42 administration order not checked,39,45,50 and an incomplete warning label.49
In 2007, a plant run by the Shanghai Pharmaceutical Company reported large-scale contamination.58 During the manufacturing process, methotrexate and cytarabine, drugs commonly administered intrathecally, were contaminated by vincristine. The factory was closed by the Chinese government and the affected drugs were recalled. Trace amounts of vincristine were believed to have been unintentionally administered to 193 patients as part of their normal IT medication regimens. Although no deaths are believed to have occurred, paralysis was common.
Management of individual cases of accidental vincristine administration is detailed in Table 2. Prompt recognition of the error and immediate instigation of CSF drainage and IT exchange appear to be the only interventions that have impacted on patient survival. In 21 of the cases, including all survivors, the error was discovered within 30 minutes. An attempt to remove vincristine from the CNS occurred in most cases. Removal was not performed in 2 patients31,35 and management was not elucidated in several other reports.29,35,42–45,48,52,53
In the initial case, Schochet et al26 exchanged 200 mL of CNS with 0.9% sodium chloride in 10-mL aliquots over the first 24 hours after vincristine administration. Dyke32 was the first to describe a more aggressive approach using CSF lavage. This consisted of CSF aspiration followed by washout for 24 hours using an exchange of lactated Ringer solution and fresh frozen plasma. Fresh frozen plasma, commonly with lactated Ringer solution, was used as part of the CSF irrigation process after vincristine aspiration in 7 cases,32,36,38,39,41,47,51 and of these, all survived bar one.39 It is believed that adding fresh frozen plasma to CSF irrigation fluid causes a rapid binding of vincristine to blood components and minimizes the neurotoxicity of vincristine.55 Several antidotes for vincristine have been proposed and undergone testing as potential modifiers of vincristine neurotoxicity, including folinic acid59,60 and glutamic acid.61 A preliminary experimental study in rabbits showed that hypochlorus acid may be of benefit in reducing vincristine neurotoxicity after IT administration.62 Strategies such as folinic acid, glutamic acid, corticosteroids, pyridoxine, vitamin B12, thiamine, and caffeine have been tried, singly or in combination, after accidental vincristine spinal administration. Their value is questionable because they have commonly been used after CSF washout and exchange.
A 25-year-old woman with non-Hodgkin lymphoma was accidentally given vindesine intrathecally.63 The error was immediately recognized and CSF washout and exchange were instigated. Neurotoxicity gradually increased to paralysis, then coma. After 6 weeks, she experienced respiratory arrest and died.
Pegylated asparaginase, scheduled for intramuscular injection, was accidentally given intrathecally in a 12-year-old boy with T-cell lymphoblastic lymphoma.64 The error was not recognized until the intramuscular injection was due to be performed as the physician had not checked the label, presuming the syringe to contain cytarabine. The patient was observed closely and no adverse effects were noted.
The European Medicines Agencies released information regarding 3 fatalities that resulted from bortezomib being inadvertently administered intrathecally rather than by the intended IV route.65 Deaths occurred when IT chemotherapy was scheduled at the same time as bortezomib. Information is lacking because these cases were reported via EudraVigilance, an electronic European reporting system for suspected adverse drug reactions, and were never published.
A young girl with ALL died after she was erroneously given IT daunorubicin.66 Despite treatment with CSF exchange and IT hydrocortisone beginning 1 hour after the incident, the patient became comatose with a flacid paraparesis and died several weeks later.
Two cases of accidental IT doxorubicin administration have been documented in the literature. In the first case, the patient experienced severe, life-threatening acute encephalopathy with high-pressure hydrocephalus.67 After placement of a ventro-peritoneal shunt, the hydrocephalus was completely reversed, which led to a progressive disappearance of the acute encephalopathy. The second patient was mistakenly administered doxorubin intrathecally instead of methotrexate.68 Cerebrospinal fluid exchange was immediately initiated, but despite this, hypoesthesia, paraparesis, and incontinence developed over 7 days. Complete paraplegia ensued, and 1 month after the incident, the patient was admitted to a spinal cord injury unit, where she resided for the next 7 months. Some recovery of neurological and functional ability was observed.
During treatment for T-cell lymphoblastic leukemia, a 5-year-old girl was administered IT dactimomycin instead of methotrexate.69 The mistake was noticed 1 hour later, and CSF washout and exchange were instituted. Hydrocortisone IT, ascorbic acid IT, and sodium thiosulfate IV were also used. Severe neurological toxicity developed rapidly. She was discharged from hospital 55 days later, without ventilatory support. After more than 2 years, paraplegia of the lower extremities, spastic paraparesis of the lower limbs, and bladder impairment still persist.
This review is based on cases reported in the English language, medical literature (accessed via Medline and Embase databases), or through citations in relevant articles. It is thought that many cases have gone unrecognized and unreported or have only been reported to adverse event databases or drug companies or published in local news sources.
Errors tend to occur because of lapses in defensive barriers. These arise because of 2 reasons, termed active failures and latent conditions.70 Active failures are unsafe acts committed by people who are in direct contact with the patient or system. Examples of active failures include IV medications being available in the area used for IT administration, IT medications being given before all other drugs in the protocol have been administered, incorrect or inadequate labeling of medications, and medical staff administering the drug by the wrong route.71 Latent conditions are inherent problems within the system that may lie dormant for many years before combining with active failures and local triggers to provide an opportunity for errors to occur. Examples of latent conditions include inexperienced or untrained staff involved in the preparation, delivery, or administration of chemotherapy; medication provided in an inappropriate form for administration; selecting an unsuitable environment or time for IT drug administration; and procedural problems such as the lack of double checking before drug preparation in pharmacy or drug administration by medical staff.71 To prevent the possibility of accidental IT administration of antineoplastic medications, both the human and system failures that could potentially occur need to be addressed. Specific recommendations have been made to reduce the risk of inadvertent IT vincristine administration.71 These strategies can be adapted to reduce the risk of medication errors associated with IT administration for both overdose and the inadvertent administration of other antineoplastic agents (Table 3).
To my knowledge, every error involving the accidental intraspinal administration of an antineoplastic agent over the past 45 years has occurred when the drug was prepared in a syringe.72 The abolishment of the syringe as a method of administration has proven the most effective approach for eliminating the potential spinal instillation of vincristine.73 Vincristine can be prepared in 50 mL of 0.9% sodium chloride and administered over 5 to 10 minutes as a short IV infusion. In children, a lesser volume of fluid and slower infusion rate can be used. This strategy works on the premise that it is impossible to administer vincristine prepared in this form via a spinal needle and has the added benefit of prompting staff to realize that something is obviously wrong if this is even attempted. Concerns that this method may increase the risk of extravasation have been voiced, but these are largely unfounded.74 When correct techniques for antineoplastic drug administration are followed, extravasation rarely occurs (<1 per 1000 IV administrations) and the consequences are significantly less than those associated with the accidental IT administration of vincristine.75 Extravasation can be prevented with the implementation of careful, standardized, evidence-based administration techniques. Preventative strategies include identification of patient-related and procedure-related risk factors, use of appropriate IV access devices (peripheral, central), thorough education of patients, and administration only by experienced trained and accredited nursing staff.76 There are advocates for increasing the volume of diluent in the syringe as a deterrent to IT vincristine administration; however, this is not a viable solution, as deaths have been reported after administration via 10-mL40 and 20-mL46 syringes. The incidence of extravasation of vinca alkaloids after administration via syringes and small-volume infusion solutions was assessed in a retrospective study of documented cases from 68 Australian hospitals.73 The reported frequency of vincristine extravasation from syringes was 0.03% and 0.041% with small-volume infusions. These data further support the use of low-volume, short infusions as the safest method of vincristine administration.
Other antineoplastic agents that have the potential to be accidentally given intrathecally could also be administered via infusion. No deaths have ever occurred when mini-bags have been used. The only agent where this is currently not feasible is bortezomib.65 Unfortunately, no current information is available on the stability of bortezomib in a mini-bag, so until reliable data exist, we are forced to continue the practice of administration via syringe. A recent noninferiority study has demonstrated that bortezomib can be given subcutaneously instead of intravenously, with no loss of efficacy and an improved toxicity profile.77 Subcutaneous administration necessitates preparation in a syringe, and in countries where this has been approved, the manufacturer provides stickers that are placed directly on the syringe after preparation to alert health professionals to the correct method of bortezomib administration.
A variety of methods for improving spinal drug delivery are being investigated. Reversing the existing direction of Leur lock connections on spinal catheters and syringes has been suggested.78 This would make it impossible to connect medications prepared in an IV syringe to a spinal needle. Purpose-built syringes or syringe caps, using printed text, shape, and color coding to designate specific use, have also been proposed.79 A Canadian group has developed a spinal injection safety system where the special filling device is not compatible with existing needles and, conversely, medication placed in Leur lock syringes is not compatible with the spinal injection safety system spinal needle.80 The Department of Health in the United Kingdom has been evaluating prototype connector systems designed to be incompatible with standard Leur equipment.81 A simulation-based evaluation of these proposed alternatives to Leur devices involving 59 experienced clinicians identified problems with the 2 systems.82 This necessitated further modifications because there were the possibility of cross-connectivity with Leur connectors and concerns about leakage and some devices were found to be not “user-friendly.” Although the development of new spinal delivery systems is admirable, they should be used only in conjunction with other strategies for prevention of IT medication errors. Syringes of any type should never be used to administer vinca alkaloids because there is still the slim possibility of mistakenly using the wrong type of syringe during the manufacturing process.
The consequences of medication errors associated with IT chemotherapy are potentially devastating. Because many of the fatalities reported have occurred in young, probably curable, patients, this is particularly distressing. Early recognition of the error and immediate treatment with CSF drainage and exchange offer the best chance of patient recovery. Currently, no readily available, effective antidote for any antineoplastic agent administered inadvertently or in overdose exists. Developing effective methods for prevention and incorporating them as standard practice internationally offer the best method for management of this problem. Nursing, medical, and pharmacy professions must work together in conjunction with hospital administrators and government bodies to ensure that guidelines for prevention are universally adopted so that these tragic errors never happen again.
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