PRACTICAL THERAPEUTICS

Drugs 41 (5): 702-716, 1991 00 12-6667/91/0005-0702/$07.50/0 © Adis International Limited. All rights reserved. DRU114

Current Pharmacological Treatment Approaches to Cenfral Nervous System Leukaemia Susan M. Blaney. Frank M. Balis. and David G. Poplack Walter Reed Army Medical Center, Washington, DC, and National Cancer Institute, Bethesda, Maryland, USA

Contents 702 704 704 705 705 705 705 706 707 707 708 708 709 709 709 709 709 710 710

710 711 711

712 713 713 713 713

714 714

Summary

Summary 1. Clinical Pharmacology of Intrathecal Chemotherapy 1.1 Intralumbar Therapy 1.2 Intraventricular Therapy 2. Intrathecal Methotrexate 2.1 Intralumbar Methotrexate 2.1.1 Dosing Considerations 2.1.2 Pharmacokinetics 2.2 Intraventricular Methotrexate 2.2.1 Pharmacokinetics 2.2.2 'Concentration X Time' 2.3 Toxicity 3. Intrathecal Cytarabine 3.1 Intralumbar Cytarabine 3.2 Intraventricular Cytarabine 3.3 Toxicity 4. Systemic Therapy 4.1 L-Asparaginase 4.2 Corticosteroids 4.3 Thiotepa 5. High-Dose Systemic Therapy 5.1 High-Dose Intravenous Methotrexate 5.2 Intravenous Cytarabine 5.3 Intravenous 6-Mercaptopurine 6. New Agents for the Treatment of Meningeal Leukaemia 6.1 Diaziquone 6.2 Intrathecal 6-Mercaptopurine 6.3 Intrathecal Mafosfamide 7. Conclusions and Future Directions for Research

Significant advances in the treatment and prevention of meningeal leukaemia have been made in the past 3 decades. This progress has resulted from the development of innovative approaches

Current Approaches to CNS Leukaemia

703

to treatment as well as a better understanding of the pharmacokinetics and pharmacodynamics of the commonly used antileukaemic agents. Intrathecal therapy, via the intralumbar or intraventricular route, is a form of regional therapy that results in the delivery of very high drug concentrations to the principal target tumour site (the meninges) using a relatively small drug dose, thereby minimising both systemic drug exposure and systemic toxicity. The dosage and schedules, clinical pharmacology and toxicities of the commonly used intrathecal agents, methotrexate and cytarabine (cytosine arabinoside; Ara-C) are discussed in detail. Another approach which has been used to overcome the poor penetration of anti leukaemic drugs into the CNS has been the use of high-dose systemic therapy. This strategy has been successfully applied in the treatment of meningeal leukaemia using both high-dose methotrexate and high-dose cytarabine. The clinical pharmacology, toxicities, and potential limitations of this approach are outlined. Finally, new agents that are currently undergoing clinical evaluation and future directions for research are also discussed.

With improvements in systemic chemotherapy for acute lymphoblastic leukaemia (ALL) and the resultant prolonged systemic remissions in children with ALL, the central nervous system (eNS) primarily the meninges - emerged as the most frequent site of initial relapse (Evans et al. 1970; Price & Johnson 1973). Prior to the incorporation of specific therapy that directly targeted disease in the eNS, the incidence of overt meningeal relapse approached 75% in patients who had achieved a bone marrow remission (Evans et al. 1970; Hardisty & Norman 1967). Leukaemic cells in the eNS are protected from the cytotoxic effects of standard systemic chemotherapy by the blood-brain barrier which blocks the entry of most antileukaemic agents into the eNS (table I). Recognition of the limitations of systemically administered chemotherapy has resulted in the development of therapeutic strategies targeted directly at the eNS. These approaches, including direct intrathecal injection of antileukaemic drugs and the use of cranial axis irradiation, produced remissions in most of the patients who developed overt meningeal disease and were therefore incorporated into frontline protocols as preventive therapy. As a result, the incidence of meningeal relapse in patients with ALL ~as reduced to less than 10% (Aur et al. 1971). Despite these impressive advances in the treatment and prevention of meningeal leukaemia, several important challenges still face the clinician. First, current standard preventive approaches in-

clude cranial irradiation, which has been associated with significant adverse neurological and nettroendocrine deficits, including impairment of intellectual function (Poplack 1983). The development of alternative therapies which are equally effective but less neurotoxic is therefore an important priority. Second, in the small percentage of patients who experience a meningeal relapse despite preventive eNS therapy, eNS leukaemia is difficult to eradicate, and the long term outcome of patients with meningeal recurrence is poor. FurTable I. CNS penetration of antileukaemic drugs expressed as the ratio of CSF to plasma drug concentration (reproduced with permission from Balis & Poplack 1989)

Drug

CSF to plasma ratio

Methotrexate 6-Mercaptopurine Cytarabine Daunorubicin (daunomycin) Vincristine Teniposide Prednisone L-Asparaginase Cyclophosphamide Parent drug Active metabolite

0.03 0.26 0.1-0.25 NDa 0.05 0.01-0.03 0.08 b NDc ND

0.17

Not detectable in CSF. CSF penetration is dose dependent; see text. Drug is not detectable in CSF, but CSF L-asparagine is depleted by systemic administration of L-asparaginase. Abbreviation: ND = not detectable. a b c

704

Drugs 41 (5) 1991

ther research to identify new agents that can be administered intrathecally, new combination intrathecal regimens, and more effective intrathecal and systemic treatment schedules are necessary. Development of such strategies which are both safe and effective requires a clear understanding of the central nervous pharmacology of antileukaemic agents.

1. Clinical Pharmacology 0/ Intrathecal Chemotherapy Direct administration of anti leukaemic drugs into the cerebrospinal fluid (CSF) was one of the first approaches taken to circumvent the limited penetration of antileukaemic agents across the blood-brain barrier. This form of regional therapy achieves high drug concentrations at the principal target tumour site, i.e. the meninges, with relatively small drug doses, because of the comparatively small initial volume of distribution in the CSF (l40ml for CSF versus 3500ml for plasma) [Collins 1987; Poplack & Riccardi 1987]. The intrathecal route therefore has the potential advantage of minimising both systemic drug exposure and systemic toxicity. Additionally, drug exposure is maximised since the drug elimination half-lives of most drugs are longer in the CSF following intrathecal administration than in the systemic circulation following a systemic dose (Pop lack et al. 1980). 1.1 Intralumbar Therapy

drugs into ventricular CSF following an intralumbar dose secondary to the slow unidirectional flow ofCSF [for example, methotrexate concentrations in the ventricles approximate only 10% of simultaneously drawn lumbar levels (Bleyer & Poplack 1978)]; (d) the alterations in CSF flow in the presence of meningeal leukaemia that interfere with the distribution and pharmacokinetic behaviour of intrathecally administered agents (Poplack et al. 1980); (e) the limited penetration of cytotoxic drug concentrations into the brain parenchyma (Blasberg et al. 1975) and, ({) the unique toxicities as-

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Intrathecal drugs are usually administered by the intralumbar route. Despite the theoretical pharmacokinetic advantages of this regional form of therapy described above, there are also inherent limitations to intralumbar administration, including: (a) the pain and inconvenience associated with r.epeated lumbar punctures; (b) the demonstration by radioisotope studies that in at least 10% oflumbar punctures the drug is not delivered to the subarachnoid space, but instead is injected or leaks into the subdural or epidural space (Larson et al. 1971); (c) the limited and variable distribution of

10- 8

10-9L-----~----_r----~------~---

2

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4

Time (hours) Fig. 1. Ventricular CSF methotrexate concentrations in a nonhuman primate maintained in the flat, Trendelenburg, and upright positions following administration of intralumbar methotrexate.

Current Approaches to CNS Leukaemia

705

sociated with intrathecal therapy such as chemical arachnoiditis. Another factor which may limit the effectiveness of intralumbar administration of chemotherapeutic agents is that ventricular drug distribution may in part be affected by patient positioning following drug administration. Studies done in nonhuman primates that were kept in a Trendelenburg, flat or upright position following intralumbar administration of methotrexate showed that ventricular levels at I hour were 1000 times higher in animals maintained in the flat or Trendelenburg position than levels achieved in animals that were maintained in the upright position (Echelberger et al. 1981) [fig. 1]. 1.2 Intraventricular Therapy Some of the limitations associated with intralumbar chemotherapy can be overcome by direct intraventricular administration of chemotherapy using an indwelling subcutaneously implanted Ommaya reservoir (fig. 2). This approach circumvents the problems of local eSF leakage or inadvertent epidural administration often associated with intralumbar dosing by ensuring direct delivery of drug into the ventricular system. Intraventricular administration also results in more complete distribution of drug throughout the eSF compartment because drug no longer has to travel against the flow of eSF, but rather is carried by eSF bulk flow through the various eSF compartments. Additionally, there is considerably less patient discomfort associated with drug administration via a reservoir which permits repetitive intraventricular injections. Despite the advantages of drug delivery via the intraventricular route, the obvious disadvantage is that it requires surgical placement of an indwelling Ommaya reservoir. This approach, therefore, is usually reserved for the treatment of patients with overt meningeal disease.

·2. Intrathecal Methotrexate 2.1 Intralumbar Methotrexate Intralumbar methotrexate, either alone or in combination with cytarabine (cytosine arabinoside; Ara-C) plus hydrocortisone (cortisol), is the

Fig. 2. Diagram of an intraventricular drug delivery system of a subcutaneously implanted Om maya reservoir attached to a catheter, the tip of which sits in the lateral ventricle (reproduced with permission from Balis & Poplack 1989).

most commonly used intrathecal agent for both the treatment and prevention of meningeal leukaemia. Remissions can be induced in over 80 to 90% of patients with overt meningeal leukaemia after administration of weekly intrathecal methotrexate (Duttera et al. 1973; Sullivan et al. 1969). Subsequent monthly administration of methotrexate generally prolongs the length of the remission. Likewise, methotrexate administered early in the induction phase of therapy, and continued throughout maintenance therapy, appears to be the optimal method for prevention of eNS leukaemia in patients with low risk ALL (Bleyer & Poplack 1985). 2.1.1 Dosing Considerations The standard methods for calculating the dose of systemic methotrexate using bodyweight or surface area are not appropriate for intrathecal metho-

706

Drugs 41 (5) 1991

100 80 CI>

§

60 ~ -'§ 40

Body surface area

-g

"# 20 0L--.-'r-'--.-'r-'--.--r-'--'--~24

Birth

4 8 Age (years)

12

16

20

Fig.3. Relationship between body surface area and CNS volume as a function of age. eNS volume increases at a more rapid rate than body surface area, achieving adult volume by 3 years of age (reproduced with permission from Bleyer et al. 1983).

trexate. As Bleyer and co-workers demonstrated, following a 12 mg/m 2 dose of intrathecal methotrexate (a dose based on body surface area), CSF methotrexate concentrations were highly variable and actually correlated better with patient age than body surface area (Bleyer 1977). They also observed that neurotoxicity was associated with higher methotrexate concentrations in the CSF, a finding more common in adults and adolescents than in young children and infants. The pharmacokinetic explanation of these observations is that the initial CSF concentration of methotrexate is determined by distribution of the drug into the extracellular fluid volume ofthe CNS. In infants and young children the CNS volume increases much more rapidly than the body surface area, so that by 3 years of age the CNS volume of the child and adult are equivalent (fig. 3) [Bleyer 1977]. Since there is not a correlation between CNS volume and body surface area, it is not surprising that there is no correlation between CSF methotrexate concentration and the dose of methotrexate administered when based on body surface area. Inirathecal methotrexate dosage regimens that were based on body surface area invariably underdosed young children because of their relatively larger CNS volume of distribution, and likewise overdosed older children and adults (fig. 4). Thus, the

current dosage recommendations for intrathecal methotrexate are based on patient age, rather than on patient weight or body surface area. This age-based dosage regimen for intrathecal methotrexate (table II) has been found to be less neurotoxic (Bleyer et al. 1983) and has also provided more consistent CSF methotrexate concentrations (Bleyer 1977; Bleyer et al. 1976). Of greater significance, however, is the fact that use of an agebased dosage regimen in CNS preventive therapy of ALL has been associated with a lower incidence of CNS relapse (Bleyer et al. 1983). This improvement has been most marked for younger patients in whom the intrathecal methotrexate dosage was increased by the new regimen. It is reasonable to assume that a similar dosing approach based on age rather than body surface area is appropriate for other intrathecally administered agents. 2.1.2 Pharmacokinetics Following a 12 mg/m 2 intralumbar dose of methotrexate, elimination is biphasic with half-lives of 4.5 and 14 hours (Bleyer & Poplack 1978). The mean lumbar CSF methotrexate concentration is greater than 10 ~mol/L at 6 hours and falls to 0.1 ~mol/L by 48 hours. However, ventricular CSF methotrexate concentrations following an intralumbar dose are quite variable (Shapiro et al. 1975), and approximate only 10% of simultaneously drawn lumbar levels (Bleyer & Poplack 1978). As shown in figure 5, CSF methotrexate concentrations are 100 times greater than plasma concentrations, illustrating one of the advantages of regional chemotherapy. However, because of the slow release of drug from CSF into the systemic circulation, the systemic exposure to methotrexate following an inTable II. Pharmacokinetically derived dosage regimen for in· tralumbar methotrexate based on patient age (reproduced with permission from Balis & Poplack 1989) Patient age (y)

Methotrexate dose (mg)

OI !l

+50 +25

CI»(

OIl!!

~~ li;a>

0

Il.E

1.5

4

7

Age (years)

Fig. 4. Percentage change in the dose of methotrexate as a function of age with the new intrathecal dosing regimen based on age (table II) relative to the dose based on body surface area. Compared to the new dosing method (age), younger patients were underdosed and adolescents were overdosed using body surface area to calculate dose (reproduced with permission from Bleyer et al. 1983).

trathecal dose is more prolonged than following an equivalent dose administered intravenously. Plasma concentrations remain above 0.01 ~mol/L for twice as long with the intrathecal dose (Bleyer & Poplack 1978). Methotrexate elimination from the cerebrospinal fluid is primarily .by bulk eSF resorption, although a nonspecific active transport system also exists (Shapiro et al. 1975). Delayed clearance of methotrexate from the eSF has been associated with a number of conditions, including the presence of meningeal leukaemia and obstructive hydrocephalus (Bleyer et al. 1983; Grossman et al. 1982; Poplack et al. 1980). Recognition of those phenomena which interfere with eSF flow through obstruction ofthe subarachnoid and/or ventricular flow pathways is important since delayed clearance of methotrexate from the eSF is associated with the occurrence of neurotoxicity (Bleyer et al. 1973). 2.2 Intraventricular Methotrexate

707

intralumbar injection. Intraventricular administration produces consistently higher ventricular eSF drug concentrations. Intraventricular therapy also appears to be more effective in the treatment of eNS leukaemia. In one study, 7 of 8 evaluable children with meningeal leukaemia treated with intraventricular methotrexate had a significantly longer duration ofCNS remission (475 days) compared to their duration of eNS remission following intralumbartherapy (286 days) with an equivalent methotrexate dose. This difference occurred despite the fact that the intraventricular therapy was administered after the children failed intralumbar therapy (Bleyer & Poplack 1979). 2.2.1 Pharmacokinetics Following an intraventricular methotrexate dose of 6.25 mg/m 2 peak concentrations are greater than 200 ~mol/L and ventricular concentrations remain above 0.2 ~mol/L for 48 hours (Shapiro et al. 1975). Methotrexate appears in the lumbar eSF by 1 hour after intraventricular injection and exceeds ven-

Lumbar

CSF

Plasma

~-~~--:-::-~~-~;:;:-~~ 40 80

10- 10+1

o

TIme

Direct intraventricular administration of methotrexate via an indwelling reservoir overcomes the problems of variable and relatively low ventricular methotrexate concentrations achieved following

(hours)

Fig. 5. Lumbar CSF and plasma methotrexate concentration in patients treated with a 12 mg/m 2 dose administered by the intralumbar route (reproduced with permission from Bleyer & Poplack 1978).

708

Drugs 41 (5) 1991

tricular CSF concentrations by 4 hours (Shapiro et al. 1975). Drug concentrations are more consistent from patient to patient following ventricular administration (Bleyer & Poplack 1978; Shapiro et al. 1975) than after intralumbar dosing. 2.2.2 'Concentration x Time' Another advantage of an indwelling ventricular access device is that it facilitates drug administration on a wide variety of schedules including the 'concentration x time' (C X T) approach (i.e. the administration of multiple low doses over a relatively short period). This strategy increases the duration of CSF exposure to cytotoxic drug concentrations and avoids excessively high peak concentrations, while at the same time reducing total drug dose (Bleyer et al. 1978). This has important therapeutic implications since the neurotoxicity associated with intrathecal methotrexate has been correlated with both the total amount of drug administered and with elevated methotrexate concentrations in the CNS (B1eyer et al. 1973; Kay et al. 1972; Norrell et al. 1974; Price & Jamieson 1975). The advantages of the C X T approach in patients with meningeal leukaemia have been demonstrated through comparison of 2 dosing schedules (fig. 6) for intraventricular methotrexate: a single-dose (12 mg/m 2) schedule versus a C X T schedule (Img every 12 hours X 6 doses) [B1eyer & Poplack 1978]. Although both schedules were equally effective in the treatment of meningeal leukaemia, the C X T approach was less neurotoxic and resulted in the delivery of a lower cumulative drug dose (Bleyer & Poplack 1978). These findings suggest that a lower dose of methotrexate should be administered via the intraventricular route than via the intralumbar route. However, the optimal intraventricular dose and schedule of administration remain to be defined.

2.3 Toxicity Acute and delayed neurotoxic reactions have been associated with intrathecal methotrexate administration (Bleyer 1981). An acute chemical

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Fig. 6. Comparison ofCSF methotrexate concentrations during intraventricular 'C x T' therapy (-) and after intraventricular injection of 12 mg/m 2 (-). The horizontal dotted line is an approximation of the therapeutically effective methotrexate concentration (reproduced with permission from Sleyer et al. 1978).

arachnoiditis is the most commonly observed toxicity. This reaction is characterised by headache, nuchal rigidity, back pain, vomiting, fever, and CSF pleocytosis. It can occur within several hours to several days following intrathecal methotrexate administration (Kaplan & Wiemik 1982). A subacute myelopathy or encephalopathy, characterised by limb weakness, cranial nerve palsies, ataxia, visual impairment, seizures, and coma, can occur within a few days to a week or more after a course of intrathecal methotrexate. This toxicity is associated with elevated CSF methotrexate levels (B1eyer et al. 1973) and with frequent drug administration (e.g. biweekly) and may be irreversible in some cases. Lastly, a chronic, progressive demyelinating encephalopathy, termed leukoencephalopathy, can occur months to years after treatment with intrathecal methotrexate and cranial irradiation (Kaplan & Wiemik 1982).

709

Current Approaches to CNS Leukaemia

3. I"trathecal Cytarabine Intrathecal cytarabine is the second most widely used intrathecal agent for the prevention and treatment of meningeal leukaemia. Cytarabine, however, is generally used as a second-line agent or in combination with methotrexate and hydrocortisone ('triple intrathecal chemotherapy'). A number of dosing schedules for intratheeal cytarabine are commonly used, but twice-weekly or weekly schedules of administration are the most widely used. The dose of cytarabine ranges from 30 to 100 mg/ m 2. Triple intrathecal chemotherapy regimens use an age-based dosing regimen for the cytarabine as well as for the methotrexate and hydrocortisone. 3.1 Intralumbar Cytarabine There is a marked difference in the disposition of cytarabine in the CSF following intrathecal compared to intravenous administration. Cytarabine in plasma is rapidly metabolised to the inactive metabolite uracil arabinoside (ara-U) by the ubiquitous enzyme cytidine deaminase (Camiener & Smith 1965). In contrast, after intrathecal injection of cytarabine, conversion to ara-U is negligible because of the significantly lower cytidine deaminase activity in the brain and CSF. This difference is responsible for the more prolonged half-life of this agent in CSF versus plasma, and favours the intrathecal route of administration. 3.2 Intraventricular Cytarabine Pharmacokinetic studies following a 30mg dose of intraventricular cytarabine reveal biphasic elimination with half-lives of 1 and 3.4 hours. Peak CSF concentrations exceed 2 mmol/L and remain above 1 ~mol/L (the minimum cytotoxic concentration in vitro) for more than 24 hours (Ho & Frei 1971; Zimm et al. I 984b). CSF clearance is similar to CSF bulk flow at a rate of 0.42 ml/min (Zimm et al. 1984). Cytarabine is not detectable in patient plasma samples following intrathecal administration (Zimm et al. 1984b). As with other antimetabolites, the duration of

exposure of neoplastic cells to cytotoxic concentrations of cytarabine is an important determinant of drug efficacy (Chabner 1982a). Thus, intraventricular administration of cytarabine using a C X T schedule has theoretical advantages. Administration of cytarabine daily for 3 days (30 mg/dose) maintains cytotoxic drug concentrations for more than 72 hours versils approximately 24 hours for a single dose of7Omg. Additionally, the daily times 3 schedule results in lower peak concentrations (Zimm et aI. 1984b). Clinical studies using the C x T approach are under way. 3.3 Toxicity Chemical arachnoiditis is the most frequent toxic reaction observed following intrathecal cytarabine administration. More serious reactions, including seizures (Eden et aI. 1978) and transient paraplegia (Wolff et al. 1979) have also been reported. The occurrence of paraplegia was reported in a patient given high intrathecal doses of the drug at frequent intervals (100 mg/m 2/day for 5 consecutive days). The association between paraplegia and the intensive dosage regimen suggests a relationship between toxicity and a high concentration of cytarabine in the CSF.

4. Systemic Therapy As outlined in table I, most antileukaemic agents do not penetrate the blood-brain barrier to a significant extent. Factors that influence CNS drug penetration include: the physicochemical properties of the drug, the degree of protein binding of the drug, and the affinity of the drug for carriers that facilitate transport of endogenous compounds into the CNS. Characteristics adversely affecting drug penetration across the blood-brain barrier include: poor lipid solubility; significant ionisation, and high molecular weight (Mellet 1977; Poplack et aI. 1980). Likewise, highly protein- or tissue-bound agents do not readily penetrate the blood-brain barrier (KoChWeser & Sellers 1976).

710

Drugs 41 (5) 1991

4.1 L-Asparaginase '0

Despite the extensive limitations to CNS penetration of most antileukaemic agents, some agents still appear to exert cytotoxic effects on leukaemic blasts in the CSF. L-Asparaginase, an antileukaemic agent that converts L-asparagine to aspartic acid, rapidly depletes the circulating pool of the nonessential amino acid L-asparagine. Since lymphoblasts lack the capacity to synthesise L-asparagine, they are dependent on exogenous pools of this amino acid to proliferate. Although L-asparaginase is not detected in the CSF following systemic administration, CSF levels of L-asparagine are nonetheless depleted for prolonged periods following systemic L-asparaginase administration (Riccardi et al. 1981). The biochemical effect observed with sytemic L-asparaginase (depletion of both systemic and CSF asparagine) therefore obviates the need for intrathecal L-asparaginase administration. Despite the fact that systemically administered L-asparaginase is capable of exerting an antileukaemic effect in the CNS, this approach has not been exploited therapeutically. When L-asparaginase has been used in ALL treatment it has been primarily for its systemic activity. 4.2 Corticosteroids The synthetic corticosteroids dexamethasone and prednisone are lympholytic agents that playa significant role in the treatment of ALL. The penetration of both agents into the CSF is low and appears to be limited by the plasma protein binding of the drugs rather than by a blood-CSF barrier (Balis et al. 1987), as evidenced by the fact that CSF drug concentrations are equivalent to free plasma drug concentration. Prednisolone (the active metabolite of prednisone) is tightly and extensively bound to the carrier protein transcortin. Transcortin binding sites are not saturated until prednisolone concentrations exceed 1 ~mol/L and binding decreases from more than 90 to 60% as the prednisolone concentration approaches 10 ~mol/L (Balis et al. 1987). In contrast, plasma protein

c:

100

~

.2 c:

'iii

80

~a. CD

'"

.l!! c:

60

~

CD

D..

40

0.1

0.01

10

100

Steroid concentration (I'mol/L)

Fig. 7. Plasma protein binding of dexamethasone (0) and prednisolone (0) as a function of plasma drug concentration (reproduced with permission from Balis et a!. 1987).

binding of dexamethasone is 70% and is independent of dexamethasone concentration (fig. 7). Extrapolating from these data, it is estimated that following a standard oral dose of prednisone, the CSF levels of prednisolone would be only onefifth to one-tenth those achievable after an equipotent dose of dexamethasone (Balis et al. 1987). Thus, there appears to be a pharmacological advantage for the use of dexamethasone rather than prednisone in the treatment of CNS leukaemia. These findings support the results of one early study in which children with ALL randomised to receive dexamethasone during induction chemotherapy had a significantly lower CNS relapse rate than those receiving prednisone (Jones et al. 1984). These results, however, require confirmation by further studies. 4.3 Thiotepa Thiotepa, an alkylating agent, has infrequently been administered by the intrathecal route for patients with meningeal leukaemia refractory to other agents. Recent pharmacokinetic studies, however, have demonstrated that, unlike other antileukaemic drugs (methotrexate and cytarabine), there does not appear to be a pharmacological advantage for this route of administration. After intrathecal injection, thiotepa drug distribution throughout the neuraxis is limited as a result ofthe rapid diffusion of drug from the CSF (thiotepa CSF

Current Approaches to CNS Leukaemia

clearance is approximately 9 times the rate of CSF bulk flow). In addition, TEPA, the active metabolite formed after systemic drug administration, is not detectable in the CSF following intrathecal administration. TEPA elimination is prolonged compared with thiotepa and the total exposure to TEPA exceeds that of thiotepa at standard doses (Strong et al. 1986). Following intravenous administration of thiotepa, both thiotepa and TEPA readily cross the blood-brain barrier and provide almost identical total drug exposure in the CSF and in plasma. Thus, the preferred route of admi'nistration for this agent is the systemic route. Clinical trials to determine the efficacy of systemically administered thiotepa for the treatment of meningeal leukaemia and CNS malignancies are in progress.

5. High-Dose Systemic Therapy

711

10-3

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Calcium folinate rescue begins

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Theoretically, therapeutic drug concentrations of antileukaemic agents that penetrate poorly into the CSF can be achieved if a high enough systemic dose of drug can be administered. The potential advantages of high-dose systemic drug administration include: (a) more uniform distribution of drug throughout the neuraxis; (b) the ability to sustain CSF drug levels for long periods of time with prolonged intravenous infusions; (c) better penetration of drug into brain tissue and deep perivascular spaces and, (d) circumvention of problems associated with improper intralumbar injection (e.g. leakage of drug from the subarachnoid space) [Balis & Poplack 1989]. The potential for severe systemic toxicity associated with the administration of high systemic drug doses is the obvious limitation to this strategy. As outlined below this approach has been successfully applied with both methotrexate and cytarabine. 5.1 High-Dose Intravenous Methotrexate Methotrexate-treated cells can be 'rescued' from the toxic effects of this agent if they are supplied with a biologically active source of folate such as calcium folinate (leucovorin calcium). With the use of calcium folinate rescue, very high systemic doses

Fig. 8. CSF and plasma methotreute (MTX) concentrations achieved with a 24-hour infusion of very high dose methotrexate, consisting of a loading dose of 6000 mg/m2 over 1 hour followed by an infusion of 1200 mgjm 2fh over 23 hours. Intensive calcium folinate rescue is initiated i12 hours after the completion of the infusion (reproduced with permission from Balis & Poplack 1989)

of methotrexate can be administered safely and therapeutic CSF methotrexate levels can be achieved despite the limited penetration of methotrexate into the CSF (CSF: plasma 0.03). Prolonged exposures to CSF cytotoxic concentrations of methotrexate as high as 30 to 40 ILmol/L can be achieved following a high-dose methotrexate regimen. In the methotrexate infusion regimen shown in figure 8, a loading dose of 6000 mg/m 2 over 1 hour is followed by an infusion of 1200 mg/m 2/h over 23 hours, giving a total dose of 33 600 mg/ m 2 over 24 hours (Balis et al. 1985). Intensive calcium folinate rescue commences 12 hours after completion of the infusion. Significant activity against meningeal leukaemia has been observed following administration of this very high dose methotrexate regimen (33 600 mg/m2). 16 of 20 patients with overt meningeal leukaemia treated according to this methotrexate regimen attained CQmplete remission and the re-

712

maining 4 patients had a greater than 90% reduction in the leukaemic blasts in the CSF (Balis et al. 1985). This regimen has also been successfully used for the prevention of meningeal leukaemia in patients with ALL, thereby eliminating the need for standard preventive therapy, cranial irradiation and intrathecal methotrexate (Poplack et al. 1984). Although regimens using very high doses of systemic methotrexate have been effective, the optimal methotrexate dose and schedule necessary for systemic therapy of CNS leukaemia have not been defined. A rational approach to dosing of systemic methotrexate for CNS treatment is to attempt to attain a CSF methotrexate concentration of greater than I ~mol/L (the optimal cytotoxic methotrexate level based on in vitro studies) for a prolonged period (i.e. up to 42 hours). Although doses as high as 33600 mg/m 2 may not be necessary, regimens with total methotrexate doses in the range of 1000 mg/m2, which yield CSF methotrexate concentrations of 0.2 to 0.3 ~mol/L, are likely to be less effective. In an attempt to circumvent the problems associated with low CSF concentrations using intermediate-dose methotrexate alone, other regimens using a combination of intermediate-dose systemic plus intrathecal methotrexate have been used. Such regimens have been shown to reduce the incidence of primary meningeal relapse in standard-risk ALL patients but have been much less efficacious in the prevention of meningeal relapse in high-risk ALL patients (Green et al. 1980). The primary toxicities associated with administration of high-dose systemic methotrexate are myelosuppression and mucositis. Nephrotoxicity secondary to precipitation of methotrexate or its primary metabolite, 7-hydroxymethotrexate, in acidic urine or secondary to direct toxic effects on the renal tubule has also been infrequently observed (Chabner I 982b), and can be avoided by vigorous intravenous hydration and alkalinisation of the urine. Hepatic toxicity consisting of transient elevation of serum transaminases and, less commonly, hyperbilirubinaemia have also been observed. Other less common toxicities include a dermatitis, characterised by erythema and desquamation, allergic reactions, and acute pneu-

Drugs 41 (5) 1991

monitis. High-dose methotrexate has also been associated with acute, subacute, and chronic neurotoxicities, particularly when given in association with cranial irradiation (Bleyer 1981; Packer et al. 1983). Methotrexate is eliminated primarily by the kidneys; approximately 70 to 90% of a dose is excreted unchanged within 6 hours of administration. Delayed clearance of methotrexate secondary to renal dysfunction can result in prolonged systemic exposure and can potentially cause severe toxicity. Therefore, patients with suspected or known renal dysfunction must have careful monitoring of plasma methotrexate concentrations and appropriate adjustment of calcium folinate doses in the event of persistently elevated methotrexate concentrations. Patients who have a creatinine clearance of 50 to 75% the normal value should not receive high-dose methotrexate. 5.2 Intravenous Cytarabine Cytarabine penetration across the blood-brain barrier is significantly greater than that of methotrexate. At a dose of 3000 mg/m 2 given every 12 hours, persistent cytotoxic concentrations of cytarabine can be achieved in the CSF. The elimination half-life of cytarabine in the CSF is 8 times greater than in plasma and CSF cytarabine levels eventually exceed plasma levels (Lopez et al. 1985; Slevin et al. 1982). As discussed earlier, this is secondary to the differences in cytidine deaminase levels in plasma and CSF. Unlike methotrexate, the CSF to plasma ratio for cytarabine appears to be dose-dependent, as was demonstrated in I study in which the CSF : plasma ratio fell from 0.33 to 0. 18 as the dose of cytarabine was increased from 4000 to 18000 mg/m 2 administered as a 72-hour continuous infusion (Donehower et al. 1986). However, despite the demonstrated efficacy of high-dose cytarabine in the treatment of meningeal leukaemia (Frick et al. 1984), this approach is associated with significant systemic toxicity. The lack of a rescue agent analogous to calcium folinate therefore limits the applicability of high-dose cytarabine therapy for the treatment of CNS leukaemia.

Current Approaches to CNS Leukaemia

The primary toxicities of cytarabine are myelosuppression, nausea, vomiting, and gastrointestinal mucositis. Children receiving standard doses of cytarabine have also been reported to have a syndrome characterised by fever, myalgia, bone pain, and occasionally by chest pain, maculopapular rash, and conjunctivitis (Castelberry et al. 1981). High-dose cytarabine regimens have also been associated with neurotoxicity characterised by cerebellar dysfunction (Barnett et al 1985; Herzig et al. 1985). This neurotoxicity appears to be dose related, with increasing symptoms in patients receiving total doses of cytarabine over 24000 mg/ m 2 (Herzig et al. 1983). The drug should be discontinued immediately with the onset of nystagmus or ataxia. 5.3 Intravenous 6-Mercaptopurine 6-Mercaptopurine, an active antileukaemic agent used in low oral doses as part of standard maintenance therapy, is not detectable in the CSF following an oral dose of 75 mg/m 2. However, when administered as a high-dose intravenous infusion (50 mg/m 2/h) the steady-state CSF to plasma ratio is 0.25. The steady-state plasma and CSF concentrations following this dosing schedule are greater than 6 and 1.5 ~mol/L, respectively. These stea9Ystate concentrations are above the known cytotoxic concentrations for leukaemic blasts in vitro (Zimm et al. 1985). Intravenous 6-mercaptopurine has been shown to be a useful adjunctive approach in the prevention of CNS leukaemia in standard risk patients with ALL (Camitta et al. 1989). Further trials to evaluate the efficacy of intravenous 6-mercaptopurine for the prevention and treatment of meningeal and other CNS malignancies are continuing.

6. New Agents for the Treatnrent of Meningeal Leukaemia

713

that appear promising for the treatment or prevention of meningeal leukaemia following systemic administration. However, in recent years the use of a nonhuman primate model with a chronically indwelling Pudenz catheter attached to a subcutaneously implanted Ommaya reservoir (Wood et al. 1977) has resulted in the identification of several promising new intrathecal agents and the development of new therapeutic strategies for the treatment of meningeal malignancy. 6.1 Diaziquone Diaziquone, an alkylating agent that was designed to have physiochemical properties to enhance CNS penetration, was found to be too myelotoxic for systemic administration (Curt et al. 1983; Ettinger et al. 1990). However, as demonstrated by preclinical studies in the nonhuman primate model, the limitations on systemic administration of this agent can be circumvented by using a regional therapeutic approach. Following direct intraventricular administration of diaziquone in nonhuman primates, the mean area under the CSF concentration-time curve in ventricular CSF was 20fold greater than following an 80-fold higher dose of intravenous diaziquone. Furthermore, despite rapid clearance from the CSF (5-fold greater than estimated CSF bulk flow), lumbar levels following intraventricular dosing were 7-fold greater than ventricular levels achieved following intravenous administration (Zimm et al. 1984a). An ongoing phase 1/11 trial of intrathecal diaziquone using 2 different schedules of administration (twice a week for 4/ weeks, and a C x T schedule - every 6 hours x 3 doses, weekly x 4) has shown significant activity for both schedules. Complete responses have been observed on both schedules in patients who have refractory meningeal disease (Zimm et al. 1987). 6.2 Intrathecal 6-Mercaptopurine

Despite significant efforts directed toward the development of new agents with physiochemical properties designed to enhance their entry into the CNS, at the present time there are no new drugs

As discussed earlier, 6-mercaptopurine is not detectable in the CSF following a standard oral dose. In addition to the high-dose intravenous

Drugs 41 (5) 1991

714

studies previously outlined, a phase I trial of intrathecal 6-mercaptopurine is also being conducted. This study has demonstrated that cytocidal in vitro 6-mercaptopurine concentrations can be readily achieved in the CSF at doses that are well tolerated. Furthermore, 4 complete responses and 3 partial responses have been observed in the first 11 patients enrolled in this phase I trial (Adamson et al. 1989). Phase II studies to evaluate intrathecal administration of both a single bolus dose and a exT schedule are in progress. 6.3 Intrathecal Mafosfamide Mafosfamide, a preactivated cyclophosphamide derivative, is another new antineoplastic agent that is currently undergoing phase I study. Unlike cyclophosphamide, mafosfamide does not require activation by hepatic microsomal enzymes to express an antitumour effect. Mafosfamide levels in excess of in vitro cytocidal levels have been attained following intrathecal administration in our nonhuman primate model at doses that were not associated with systemic or neurotoxicity (Arndt et al. unpublished data). Mafosfamide is therefore a promising new agent for intrathecal administration.

7. Conclusions and Future Directions for Research Many improvements have been made in both the treatment and the prevention of meningeal leukaemia during the past 3 decades. However, despite this progress, continued investigation is required to improve the long term outcome of patients with overt meningeal leukaemia and to minimise potential neurotoxicities. Additional agents suitable for intrathecal administration must be identified, as well as agents with characteristics of blood-brain barrier penetration that make them desirable for systemic use. In recent years use of a nonhuman primate model has permitted the development of several promising new intrathecal agents (e.g. diaziquone, mafosfamide, and 6-mercaptopurine) that are cur-

rently being evaluated in clinical trials. In addition, this model is facilitating the development of more effective methods of drug delivery. These methods are designed to maximise tumour exposure to cytocidal drug concentrations while at the same time minimising toxicities that have been associated with high peak drug levels. Examples of such approaches that hold promise for eventual therapeutic application include continuous intraventricular infusions (Balis et al. 1989) and multi vesicular liposomes for slow-release intrathecal therapy (Kim et al. 1987). Furthermore, multiple drug combinations, the mainstay of treatment of systemic malignancies, must also be developed for the treatment of meningeal leukaemia. Finally, new modalities such as haematopoietic growth factors as adjuvants to systemic chemotherapy may, by ameliorating myelosuppressive toxicity, permit the administration of higher doses of systemic chemotherapy. This would provide a mechanism for achieving higher drug levels in the CSF for many agents whose present systemic use in the treatment of meningeal leukaemia is limited by bone marrow toxicity.

References Adamson PC, Arndt CA, Balis FM, Tartaglia RL, Gillespie AF, et al. Intrathecal mercaptopurine: phase 1/11 trial and CSF pharmacokinetic study in children with refractory meningeal leukemia. Proceedings of the American Society for Clinical Oncology 8: 213, 1989 Aur RJA, Simone JV, Hustu HO, Walters T, Borella L, et al. Central nervous system therapy and combination chemotherapy of childhood lymphocytic leukemia. Blood 37: 272-281 , 1971 Balis FM, Lester CM, Chrousos GP, Heideman RL, Poplack 00. Differences in cerebrospinal fluid penetration of corticosteroids: possible relationship to the prevention of meningeal leukemia. Journal of Clinical Oncology 5: 202-207, 1987 Balis F, McCully C, Bacher J, Poplack 00. Continuous intrathecal infusion of methotrexate. Proceedings of the American Society for Clinical Oncology 8: 72, 1989 Balis FM, Poplack 00. Central nervous pharmacology of antileukemic drugs. American Journal of Pediatric Hematology and Oncology II : 74-86,1989 Balis FM, Savitch JL, Bleyer BA, Reaman GH, Poplack 00. Remission induction of meningeal leukemia -with high-dose intravenous methotrexate. Journal of Clinical Oncology 3: 485-489, 1985 Barnett MJ, Richards MA, Ganesan TS, Waxman JH, Smith BF, et aI. Central nervous system toxicity of high-dose cytosine arabinoside. Seminars in Oncology 12 (Suppl. 3): 227-232, 1985 Blasberg RG, Patlak C, Fernstermacher JD. Intrathecal chemotherapy. brain tissue profiles after ventriculo-cisternal perfu-

Current Approaches to CNS Leukaemia

sion. Journal of Pharmacology and Experimental Therapeutics 195: 73-83, 1975 Bleyer WA. Clinical pharmacology of intrathecal methotrexate. II. An improved dosage regimen derived from age-related pharmacokinetics. Cancer Treatment Reports 61: 1419-1425, 1977 Bleyer WA. Neurologic sequelae of methotrexate and ionizing radiation: a new classification. Cancer Treatment Reports 65 (Suppl. I): 89-98, 1981 Bleyer WA, Coccia PF, Sather HN, Level C, Lukens J, et al. Reduction in central nervous system leukemia with a pharmacokinetically derived intrathecal methotrexate dosage regimen. Journal of Clinical Oncology I: 317-325, 1983 Bleyer WA, Drake JC, Chabner BA. Neurotoxicity and elevated cerebrospinal fluid methotrexate concentration in meningeal leukemia. New England Journal of Medicine 289: 770-773, 1973 Bleyer WA, Poplack DG. Clinical studies on the central-nervoussystem pharmacology of methotrexate. In Pinedo HM (Ed.) Clinical pharmacology of anti-neoplastic drugs, pp. 115-131, Elsevier/North-Holland Biomedical, Amsterdam, 1978 Bleyer WA, Poplack DG. Intraventricular versus intralumbar methotrexate for central-nervous-system leukemia: prolonged remission with the Ommaya reservoir. Medical and Pediatric Oncology 6: 207-213, 1979 Bleyer WA, Poplack DG. Prophylaxis and treatment of leukemia in the central nervous system and other sanctuaries. Seminars in Oncology 12: 131-148, 1985 Bleyer WA, Poplack DG, Simon RM , Henderson ES, Leventhal BG, et al. 'Concentration x time' methotrexate via a subcutaneous reservoir: a less toxic regimen for intraventricular chemotherapy of central nervous system neoplasms. Blood 51: 835-842, 1978 Bleyer WA, Savitch JL, Holcenberg JS. An improved regimen for intrathecal chemotherapy. Clinical Pharmacology and Therapeutics 19: 103, 1976 Camiener GW, Smith CG. Studies of the enzymatic deamination of cytosine arabinoside. I. Enzyme distribution and species specificity. Biochemical Pharmacology 14: 1405-1416, 1965 Camitta B, Leventhal B, Lauer S, Adair S, Casper J, et al. Intermediate-dose intravenous methotrexate and mercaptopurine therapy for non-T, non-B acute lymphocytic leukemia of childhood: a Pediatric Oncology Group Study. Journal of Clinical Oncology 7: 1539-1544, 1989 Castleberry RP, Crist WM, Holbrook T, Malluh A, Gaddy D. The cytosine arabinoside (ara-C) syndrome. Medical Pediatric Oncology 9: 257-264, 1981 Chabner BA. The role of drugs in cancer treatment. In Chabner B (Ed.) Pharmacologic principles of cancer treatment, pp. 314, WB Saunders Co., Philadelphia, 1982a Chabner BA. Methotrexate. In Chabner B (Ed.) Pharmacologic principles of cancer treatment, pp. 229-255, WB Saunders Co., Philadelphia, 1982b Collins JM. Regional therapy: an overview. In Poplack DG, et al. (Eds) The role of pharmacology in pediatric oncology, pp. 125-135, Martinus Nijhoff, Boston, 1987 Curt GA, Kelley JA, Kufta CV, Smith BH, Kornblith PL, et al. Phase II and pharmacokinetic study of aziridinylbenzoquinone [2,5-diaziridinyl-3,6-bis( carboethoxyamino )-1 ,4-benzoquinone, diaziquone, NSC 182986] in high-grade gliomas. Cancer Research 43: 6102-6105, 1983 Donehower RC, Karp JE, Burke PJ. Pharmacology and toxicity . of high-dose cytarabine by 72-hour continuous infusion. Cancer Treatment Reports 70: 1059-1065, 1986 Duttera MJ, Bleyer WA, Pomeroy TC, Leventhal CM, Leventhal BG. Irradiation, methotrexate toxicity, and the treatment of meningeal leukemia. Lancet 2: 703-707, 1973 Echelberger CK, Riccardi R, Bleyer A, Levine AS, Poplack DG. Influence of body position on ventricular cerebrospinal fluid methotrexate concentration following intralumbar administra-

715

tion. Proceedings,ofthe American Society of Clinical Oncology 22: 365, 1981 Eden OB, Goldie W, Wood T, Etcubanas E. Seizures following intrathecal cytosine arabinoside in young children with acute lymphocytic leukemia. Cancer 42: 53-58, 1978 Ettinger U, Ru N, Krailo MD, Ruccione KS, Krivit WA, et al. A phase II study of diaziquone in children with recurrent or progressive solid tumors: report from the Children's Cancer Study Group. American Journal of Pediatric Hematology/Oncology 12: 301-305, 1990 Evans AE, Gilbert ES, Zandstra R. The increasing incidence of central nervous system leukemia in children. Cancer 26: 404409, 1970 Frick J, Ritch PS, Hansen RM, Anderson T. Successful treatment of meningeal leukemia using systemic high-dose cytosine arabinoside. Journal of Clinical Oncology 2: 365-368, 1984 Green DM, Freeman A, Sather HN, Sallan SE, Nesbit ME, et al. Comparison of three methods of central-nervous sytem prophylaxis in childhood acute lymphocytic leukemia. Lancet 1: 1398-1402, 1980 Grossman SA, Trump DL, Chen DCP, Thompson G, Camargo EE. Cerebrospinal fluid flow abnormalities in patients with neoplastic meningitis: an evaluation using IIIIndium-DTPA ventriculography. American Journal of Medicine 73: 641-647, 1982 Hardisty RM, Norman PM. Meningeal leukemia. Archives of Disease in Childhood 42: 441-447, 1967 Herzig RH, Lazarus HM, Herzig GP, Coccia PF, WolffSN. Central nervous system toxicity with high-dose cytosine arabinoside. Seminars in Oncology 12 (Suppl. 3): 233-236, 1985 Herzig RH, Wolff SN, Lazarus HM, Phillips GL, Karanes C, et al. High-dose cytosine arabinoside therapy for refractory leukemia. Blood 62: 361-369, 1983 Ho DHW, Frei E. Clinical pharmacology of I-B-D-arabinofuranosyl cytosine. Clinical Pharmacology and Therapeutics 12: 944-954, 1971 Jones B, Shuster JJ, Holland JF. Lower incidence of meningeal leukemia when dexamethasone is substituted for prednisone in the treatment of acute lymphocytic leukemia: a late followup. Proceedings of the American Society for Clinical Oncology 3: 191, 1984 Kaplan RS, Wiernik PH. Neurotoxicity of antineoplastic drugs. Seminars in Oncology 9 (1): 103-130, 1982 Kay HEM, Knapton PJ, O'Sullivan JP, Wells DG, Harris RF, et al. Encephalopathy associated with methotrexate therapy. Archives of Disease in Childhood 47: 344-354, 1972 Kim S, Kim DJ, Geyer MA, Howell SB. Multivesicular liposomes containing I-B-D-arabinofuranosylcytosine for slow-release intrathecal therapy. Cancer Research 47: 3935-3937, 1987 Koch-Weser J, Sellers EM. Binding of drugs to serum albumin. New England Journal of Medicine 294: 311-316, 1976 Larson SM, Schall GL, DiChiro G. The influence of previous lumbar puncture and pneumoencephalography on the incidence of unsuccessful radioisotope cisternography. Journal of Nuclear Medicine 12: 555-557, 1981 Lopez JA, Nassif E, Vannicola P, Krikorian JG, Agarwal RP. Central nervous system pharmacokinetics of high-dose cytosine arabinoside. Journal of Neuro-Oncology 3: 119-124, 1985 Mellet LB. Physiochemical considerations and pharmacokinetic behavior in delivery of drugs to the central nervous system. Cancer Treatment Reports 61: 527-531, 1977 Norrell H, Wilson CB, Slagel DE, Clark DB. Leukoencephalopathy following the administration of methotrexate into the cerebrospinal fluid in the treatment of primary brain tumors. Cancer 33: 923-932, 1974 Packer RJ, Grossman RI, Belasco JB. High dose methotrexateassociated acute neurologic dysfunction. Medical and Pediatric Oncology 11: 159-161, 1983 Poplack DG. Evaluation of central nervous system prophylaxis

716

in acute lymphoblastic leukemia. In Mastrangelo R, et al. (Eds) Central nervous system leukemia: prevention and treatment pp. 95-103, Martinus-Nijhoff, Boston, 1983 Poplack DG, Bleyer WA, Horowitz ME. Pharmacology of antineoplastic agents in cerebrospinal fluid. In Wood JH (Ed.) Neurobiology of cerebrospinal fluid. vol. II, pp. 561-578, Plenum Press, New York, 1980 Poplack DG, Reaman GH, Bleyer WA, Miser J, Feusner J, et al. Central nervous system preventive therapy with high dose methotrexate in acute lymphoblastic leukemia: a preliminary report. Proceedings of the American Society for Clinical Oncology 3: 204, 1984 Poplack DG, Riccardi R. Pharmacologic approaches to the treatment of central nervous system malignancy. In Poplack DG, et al. (Eds) The role of pharmacology in pediatric oncology, pp. 137-156, Martinus Nijhoff, Boston, 1987 Price RA, Jamieson PA. The central nervous system in childhood leukemia. II. Sub-acute leukoencephalopathy. Cancer 35: 306318, 1975 Price RA, Johnson WW. The central nervous system in childhood leukemia. I. The arachnoid. Cancer 31: 520-533, 1973 Riccardi R, Ho1cenberg JS, Glaubiger DL, Wood JH, Poplack DG. L-Asparaginase pharmacokinetics and asparagine levels in cerebrospinal fluid of Rhesus monkeys and humans. Cancer Research 41: 4554-4558, 1981 Shapiro WR, Young OF, Mehta M. Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. New England Journal of Medicine 293: 161-166, 1975 Slevin ML, Piall EM, Aherne GW, Johnston A, Lister TA. The pharmacokinetics of cytosine arabinoside in the plasma and cerebrospinal fluid during conventional and high~ose therapy. Medical and PedJatric Oncology 10 (Suppl. I): 157-168, 1982 Strong JM, Collins JM, Lester C, Poplack DG. Pharmacokinetics

Drugs 41 (5) 1991

of intraventricular and intravenous N,N',N" -triethylenethiophosphoramide (thiotepa) in Rhesus monkeys and humans. Cancer Research 46: 610 1-61 04, 1986 Sullivan MP, Vietti TJ, Fernbach OJ, Griffith KM, Haddy TB, et al. Clinical investigations in the treatment of meningeal leukemia: radiation therapy regimens vs. conventional intrathecal methotrexate. Blood 34: 301-319, 1969 WolffL, Zighelboim J, Gale RP. Paraplegia following intrathecal cytosine arabinoside. Cancer 43: 83-85, 1979 Wood JH, Poplack DG, Bleyer WA, Ommaya AK. Primate model for the chronic study of intraventricularly or intrathecally administered drug and intracranial pressure. Science 195: 499501, 1977 Zimm S, Collins JM, Curt GA, O'Neill 0, Poplack DG. Cerebrospinal fluid pharmacokinetics of intraventricular and intravenous aziridinylbenzOQuinone. Cancer Research 44: 16981701, 1984a Zimm S, Collins JM, Miser J, Chatterji 0, Poplack DG. Cytosine arabinoside cerebrospinal fluid kinetics. Clinical Pharmacology and Therapeutics 35: 826-830, 1984b Zimm S, Ettinger U, Ho1cenberg JS, Kamen BA, Vietti TJ, et al. Phase I and clinical pharmacological study of mercaptopurine administered as a prolonged intravenous infusion. Cancer Research 45: 1869-1873, 1985 Zimm S, Holcenberg J, Balis F, Doherty K, Poplack DG. Intrathecal diaziquone: a new, clinically useful agent for the treatment of meningeal neoplasia. Proceedings of the American Association for Cancer Research 28: 190, 1987

Correspondence and reprints: Dr David G. Pop/ack, Head, Leukemia Biology Section, Pediatric Branch, Building 10, Room 13N240, National Cancer Institute, Bethesda, MD 20892, USA.

Errata yol. 40, No.3, 1990: To accurately reflect the data presented in the main body of the text the following amendments to the Summary of teicoplanin should be noted: Page 450: Since most patients were also receiving aminoglycosides, the last sentence of the second paragraph of the synopsis should finish with ' ... are maintained, and concomitant administration of aminoglycosides makes causality difficult to assess.' Page 451: The final sentence of the third paragraph should end ' ... that teicoplanin may be primarily bacteriostatic against enterococci. '