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© 1999 American Society for Clinical Oncology Randomized Trial of a Slow-Release Versus a Standard Formulation of Cytarabine for the Intrathecal Treatment of Lymphomatous MeningitisFrom the Department of Medicine, Brown University School of Medicine, Providence, RI; Department of Hematology/Oncology, University of Chicago, Department of Neurology, Northwestern University Medical School, Illinois Masonic Cancer Center, and Rush Cancer Institute, Chicago, IL; Department of Neuro-Oncology, M.D. Anderson Cancer Center, Houston, TX; Department of Neurology, Barrow Neurologic Institute, Phoenix, AZ; Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; Department of Neurology, Wayne State University, Detroit, MI; Department of Neuro-oncology, Massachusetts General Hospital, Boston, MA; University of California, San Diego Cancer Center, and Sidney Kimmel Cancer Center, La Jolla, CA; University of Florida Cancer Center, Gainesville, FL; University of Maryland Cancer Center, Baltimore, MD; University of Nebraska Cancer Center, Omaha, NE; Chiron Corporation, Emeryville, CA; and Skye Pharma, Inc, San Diego, CA. Address reprint requests to Stephen B. Howell, MD, Department of Medicine 0058, University of California at San Diego, La Jolla, CA 92093; email showell{at}ucsd.edu
PURPOSE: To evaluate the efficacy and safety of a slow-release formulation of cytarabine (DepoCyt; Chiron Corp, Emeryville, CA, and Skye Pharma, Inc, San Diego, CA) that maintains cytotoxic concentrations of cytarabine (ara-C) in the CSF of most patients for more than 14 days. PATIENTS AND METHODS: Twenty-eight patients with lymphoma and a positive CSF cytology were randomized to receive DepoCyt 50 mg once every 2 weeks or free ara-C 50 mg twice a week for 1 month. Patients whose CSF cytology converted to negative and who did not have neurologic progression received an additional 3 months of consolidation therapy and then 4 months of maintenance therapy. All patients received dexamethasone 4 mg orally bid on days 1 through 5 of each 2-week cycle. RESULTS: The response rate was 71% for DepoCyt and 15% for ara-C on an intent-to-treat basis (P = .006). All of the patients on the DepoCyt arm but only 53% of those on the ara-C arm were able to complete the planned 1-month induction therapy regimen. Time to neurologic progression and survival trended in favor of DepoCyt (median, 78.5 v 42 days and 99.5 v 63 days, respectively; P > .05). DepoCyt treatment was associated with an improved mean change in Karnofsky performance score at the end of induction (P = .041). The major adverse events on both arms were headache and arachnoiditis, which were often caused by the underlying disease. CONCLUSION: DepoCyt injected once every 2 weeks produced a high response rate and a better quality of life as measured by Karnofsky score relative to that produced by free ara-C injected twice a week.
LYMPHOMATOUS meningitis is a devastating complication of systemic lymphoma that is almost always incurable. The overall frequency of this complication has been defined on the basis of prospective trials from the Southwest Oncology Group1 and retrospective reviews of large single-institutional series2-9 and ranges from 3.7% to 25%. Control of the meningeal disease is necessary to preserve quality of life but is not sufficient for long-term survival, because the survival of patients is primarily determined by the extent of control of the systemic component of their disease.6,7,10 Thus effective treatment of lymphomatous meningitis requires management of both the meningeal and systemic components of the disease. The development of lymphomatous meningitis almost always heralds progressive neurologic deterioration and a fatal outcome. Very few long-term survivors have been reported from any series3,6-8,10,11 Therefore, the goal of therapy is palliation and includes relief of existing neurologic signs and symptoms and prolongation of neurologic symptom-free survival. Standard therapy for lymphomatous meningitis consists of radiation to sites of radiographically visible disease and the intrathecal (IT) administration of chemotherapy with either cytarabine (ara-C) or methotrexate (MTX). Where compatible with planned systemic therapy, some centers also use high-dose intravenous (IV) ara-C or MTX. There have been no controlled trials of any form of therapy for lymphomatous meningitis, and there have been no prospective phase II trials in which all patients were evaluated and treated in the same way. Ara-C is a cell cycle phase–specific agent for which cytotoxicity is a function of both drug concentration and duration of exposure. Maximum tumor cell kill is attained by maintaining effective concentrations in the microenvironment of the cancer cell for prolonged periods of time.12 DepoCyt (Chiron Corp, Emeryville, CA, and Skye Pharma, Inc, San Diego, CA) is a slow-release formulation of ara-C developed for the treatment of neoplastic meningitis. Whereas a single injection of free ara-C maintains cytotoxic concentrations in the CSF for less than 24 hours,13 a single injection of 50 mg of DepoCyt maintains cytotoxic concentrations of ara-C in the CSF in most patients for more than 14 days, and the drug is well distributed throughout the CSF.14 Thus IT administration of DepoCyt is required only once every 2 weeks. DepoCyt consists of ara-C encapsulated in aqueous chambers of a matrix that is composed of lipids similar to those normally found in human cell membranes (phospholipids, triglycerides, and cholesterol). The matrix is formed into spherical particles approximately 20µm in diameter that are suspended in saline. DepoCyt has the consistency and appearance of skim milk and can be injected easily through even a 28-gauge needle. When stored at 2° to 8°C, the particles are stable; when injected into the CSF, they spread throughout the neuraxis and slowly release ara-C. The particles gradually degrade and disappear from the CSF, and the lipids enter the normal lipid metabolic pathways in the body.15 Current therapy for lymphomatous meningitis has a number of limitations. Even when injected two to three times per week, treatment with free ara-C does not produce optimal CSF exposure. More frequent IT injections are desirable, but this requires more lumbar punctures or more Ommaya reservoir penetrations. The need for two to three injections per week negatively impacts the well-being of the patient and the ability of the physician to provide treatment. DepoCyt was developed with the goal of prolonging the duration of CSF exposure based on the well-established principle that the extent of tumor cell kill produced by ara-C increases with both concentration and duration of exposure.12 We report here the results of a randomized prospective trial of DepoCyt administered IT once every 2 weeks versus free ara-C injected IT twice a week for the treatment of lymphomatous meningitis.
Study Design This was an open-label, randomized, parallel-group multicenter trial in which patients with cytologically documented lymphomatous meningitis were treated with either IT DepoCyt or with IT free ara-C. Patients were stratified by whether or not their lymphoma was AIDS-related. Within each of these two strata, all patients meeting the eligibility criteria were centrally randomized between treatments in a 1:1 ratio following the Moses-Oakford algorithm.
Patients
IT Chemotherapy
One patient on the ara-C arm was unable to receive IT treatment after randomization because of the development of neutropenia associated with systemic chemotherapy. All other patients received study drug as prescribed by the protocol. One patient on the DepoCyt arm received concurrent high-dose ara-C and MTX in addition to IT DepoCyt; this was considered a protocol violation that rendered him nonassessable for response.
Clinical and Laboratory Monitoring Patients were scored as responders if their CSF cytology converted from positive to negative at all sites previously shown to be positive and they remained neurologically stable at the time of the CSF examination. Patients were scored as nonresponders if they had a positive or suspicious cytology at the end of the induction period (day 29), or if they suffered neurologic progression despite having a negative cytology. All patients who received study drug after randomization were included in the intent-to-treat analysis. Patients were considered assessable for response if they received the drug to which they were randomized, completed at least one cycle of treatment, did not receive concurrent high-dose ara-C or MTX, and had at least one CSF cytologic examination documenting conversion from positive to negative at all sites previously known to be positive. Identification of episodes of arachnoiditis was based on a standardized algorithm. Patients were scored as having drug-related arachnoiditis if, within 4 days of drug injection, they developed either neck rigidity, neck pain, or meningismus, or if they developed any two of the following signs or symptoms at the same time: nausea, vomiting, headache, fever, back pain, or aseptic CSF pleocytosis. Arachnoiditis was graded on the basis of the highest grade of any of the constellation of adverse events captured by the algorithm as mild (grade 1), moderate (grade 2), severe (grade 3), or life-threatening (grade 4).
Statistical Analysis
Fourteen patients were randomized to each arm. Only one patient enrolled on this study received drug via LP; all of the others received drug via the IVT route through an Ommaya reservoir. The median follow-up period was 87 days with a range of 13 to 1,121 days. Table 1 shows that the two treatment arms were well balanced for baseline characteristics of possible prognostic significance in lymphomatous meningitis, including age, sex, race, presence or absence of AIDS, and Karnofsky performance status. There was some imbalance in the number of patients receiving concurrent systemic chemotherapy; however, it is not clear whether the need for concurrent systemic chemotherapy is an adverse or favorable prognostic factor. On the one hand, it may reflect more extensive and advanced disease; on the other, it is remotely possible that systemic therapy with the standard-dose programs used to treat these patients supplemented the activity of the IT-administered drug. In any case, no association between any of these parameters and the measures of efficacy were found.
All of the patients randomized to DepoCyt received the drug; one patient randomized to free ara-C did not receive the drug due to the development of neutropenia associated with systemic chemotherapy. On an intent-to-treat basis, 10 (71%) of the 14 patients treated with DepoCyt attained a response, whereas two (15%) of the 13 patients treated with free ara-C attained a response (P < .006). Calculated on the basis of only the assessable patients, the response rate was 10 (77%) of 13 patients for DepoCyt and two (22%) of nine patients for ara-C (P < .027). Patients who attained a response on the basis of the local cytopathologist's interpretation of the CSF cytology examination at the end of the induction phase were candidates to remain on study and receive additional therapy. As shown in Fig 2, patients on the DepoCyt arm received a total of 74 cycles (median, 5.5 cycles/patient), whereas the patients on the ara-C arm received a total of 44.5 cycles (median, 2.5 cycles/patient). Among the 14 patients on the DepoCyt arm who actually received the drug, all (100%) were able to complete the planned 1-month induction therapy, and seven stayed on treatment all the way through consolidation. Among the 13 patients on the ara-C arm who actually received the drug, only seven (53%) were able to complete the planned 1-month induction therapy, and only three remained on treatment all the way through the consolidation phase. It is important to note that these differences result not only from the difference in the activity of the two drugs but also from the fact that only patients who attained a response on the basis of the local cytopathologist's interpretation were candidates to receive consolidation therapy.
Time to neurologic progression was defined as the time between the first day of study treatment and the day the patient was scored as suffering neurologic progression on the basis of the physician's global assessment of neurologic status, or until death, whichever came first. Because of the rarity of lymphomatous meningitis, this study was not powered to detect a difference in time to neurologic progression; however, Fig 3 shows that there was a trend toward an increase in time to neurologic progression in patients receiving DepoCyt as compared with free ara-C. The median times to neurologic progression for patients on the DepoCyt and free ara-C arms were 78.5 and 42 days, respectively. Due to the fact that some neurologic findings worsened whereas others improved, no credible determination of the fraction of patients whose neurologic status improved could be made. Figure 4 shows Kaplan-Meier plots of overall survival. Median survival was 99.5 days for DepoCyt-treated patients and 63 days for ara-C–treated patients. These differences are not statistically significant.
Data on change in Karnofsky score between baseline and the end of the induction were available for 13 of the patients on the DepoCyt arm and eight patients on the ara-C arm. The median pretreatment Karnofsky score was 70 for both groups. Table 2 shows that scores worsened in 15% of the DepoCyt-treated patients and 57% of the free ara-C–treated patients. The mean improvement in score was +3.85 on the DepoCyt arm and -8.75 on the ara-C arm (P = 0.041). This difference favored DepoCyt despite the fact that it may have been biased in favor of free ara-C by the fact that the patients for whom data were not available were the patients who had experienced disease progression before the end of induction and would be expected to have experienced the largest decrements in performance status.
Table 3 presents information on the adverse events that occurred during this trial. Most events were transient and resolved by the end of the treatment cycle on which they occurred. There was no evidence of cumulative toxicity of DepoCyt. The only adverse event that occurred in more than 10% of treatment cycles was headache. Consistent with the much greater CSF exposure to ara-C produced by DepoCyt, headache was more frequent on the DepoCyt arm than the free ara-C arm (27% v 2% of cycles). However, when it occurred, headache was generally of low grade and was adequately managed with aspirin or acetaminophen. Grade 3 headache occurred on only 5% of the DepoCyt cycles, and this grade of headache occurred in only four (29%) of the 14 patients. Six of the 14 patients reported no headache at all during DepoCyt treatment. When it occurred as an isolated episode, median duration of headache was less than 1 day. Analgesics of any kind were used on 34% of the DepoCyt cycles and 49% of the free ara-C cycles; opioids were used on 31% and 34% of cycles for DepoCyt and free ara-C, respectively.
Arachnoiditis can be caused by either tumor infiltration of the meninges or IT administration of drugs, and it is often difficult to distinguish between these two causes. It is also an expected complication of any form of IT chemotherapy. Arachnoiditis of any grade occurred on 22% of DepoCyt cycles and 13% of free ara-C cycles; it was grade 3 on 8% of DepoCyt cycles and 7% of free ara-C cycles. There were no episodes of grade 4 arachnoiditis. No patient went off study because of arachnoiditis. Among the patients on the DepoCyt arm who developed an episode of arachnoiditis, 78% went on to receive additional cycles of treatment, and the number of cycles ranged from two to nine (median, five cycles). The percentage of days on study during which the patients received glucocorticoids was similar on the two arms: 48% for the DepoCyt-treated patients and 51% for the free ara-C–treated patients. Only two patients on the DepoCyt arm and one on the free ara-C arm discontinued treatment in association with an adverse event; in none of these cases was the adverse event clearly caused by the treatment. In the DepoCyt-treated patients, these events were the development of hydrocephalus in one patient and hearing loss in the other patient; in the free ara-C-treated patient, the event was development of arm paresthesias.
When free ara-C is injected into a lateral ventricle, it has a half-life of only 3.4 hours, and cytotoxic concentrations of ara-C are maintained for only approximately 24 hours.13 Clearance is so rapid that the ara-C does not have time to spread evenly throughout the CSF. In contrast, when DepoCyt is injected into a lateral ventricle, the particles spread out evenly throughout the neuraxis so that the particle count is the same in the ventricle and lumbar sac within 24 hours of injection.14 After injection of 50 mg of DepoCyt, the free ara-C concentration declines with a terminal half-life of 141 hours, and cytotoxic concentrations are present in both the ventricular and lumbar sac CSF in most patients for more than 14 days.14 Thus DepoCyt produces a pharmacokinetic profile in the CSF that has long been sought. This is the first randomized controlled trial ever performed for any drug in patients with lymphomatous meningitis. It was designed as a randomized phase II study because of the rarity of lymphomatous meningitis, and, as such, it was not powered to detect differences between the two arms of the study unless these differences were quite large. The finding that a significant difference in response rates was observed supports the concept that prolonging the duration of CSF exposure does in fact substantially increase the effectiveness of ara-C in this disease. This is further supported by the observation that DepoCyt-treated patients experienced a trend toward a longer time to neurologic progression. Additional support comes from the analysis of change in Karnofsky performance score. In the absence of effective control of the meningeal component of the disease, patients with lymphomatous meningitis are expected to suffer progressive deterioration in Karnofsky performance score, and such a decrease was observed in the patients on the free ara-C arm. In contrast, the DepoCyt-treated patients had a small but significant improvement in their quality of life as measured by change in Karnofsky performance score over the first two cycles of therapy. Nevertheless, this was a relatively small and unblinded trial, and thus one must be cautious in interpreting the results. The response rate of 15% for the free ara-C treatment arm is lower than might have been expected on the basis of prior reports16-18; however, the criteria for response were far more stringent in this study that in any series previously reported in that cytologic conversion was required at all sites previously known to be positive, no neurologic progression was permitted, and responses were scored on the basis of central cytology review. All patients in this trial received concurrent dexamethasone. Although dexamethasone by itself may possibly have some cytotoxic activity, treatment with this drug alone is not generally considered adequate therapy for lymphomatous meningitis. In any case, the dexamethasone exposure was nearly identical for patients on both arms of the study. The most common adverse events on both arms of the study were those anticipated on the basis of prior experience with IT chemotherapy and consisted of headache, nausea, and vomiting. These occurred together most commonly as part of an episode of arachnoiditis. All of these symptoms can be caused by tumor infiltration of the meninges, and it is often not possible to clearly distinguish between disease-related and treatment-related symptoms. Nevertheless, there was a higher incidence of headache among the DepoCyt-treated patients. Grade 3 headache was infrequent, and all headaches of any grade tended to be transient in nature. This was also true of arachnoiditis. When arachnoiditis occurred, it was generally of low grade, was well managed with an increase in dexamethasone dose, and resolved in time to permit on-schedule administration of the next dose of DepoCyt or free ara-C. The observation that differences in the frequency of serious toxicities were small is corroborated by the fact that both nonopioid and opioid analgesic use and the percentage of days during which patients received glucocorticoids of any type were nearly the same for patients on both treatment arms. In addition to its better response rate, the fact that DepoCyt requires only one fourth to one sixth as many IT injections as standard free ara-C therapy is an important advantage. This less demanding injection schedule has the potential of reducing the discomfort associated with LPs or Ommaya reservoir penetrations and the complications that can ensue from these types of injections. Also of particular importance for these patients, who are often quite sick and may have neurologic deficits that impair mobility, is the fact that fewer visits to the physician are likely to be required. Finally, the less frequent injection schedule is favorable to quality of life, as it is easier to manage the emotional turmoil and functional disruption produced by the disease and its treatment when there is a 2-week break between doses. Currently ongoing trials of DepoCyt are focused on defining a dose appropriate for use in children and determining the benefit that it offers patients with solid tumor neoplastic meningitis. Additional studies will be required to determine its activity in the treatment of leukemic meningitis and its value as prophylactic therapy in patients with leukemia and lymphoma who are at particularly high risk of developing meningeal involvement, as well as to better define the safety profile and overall benefit of this drug.
Supported by the Chiron and DepoTech Corporations. We acknowledge the assistance of G. Berry Schumann, MD, who served as the blinded cytologist for this trial.
1. Herman TS, Hammond N, Jones SE, et al: Involvement of the central nervous system by non-Hodgkin's lymphoma. Cancer43:390-397, 1979[Medline] 2. Young RC, Howser DM, Anderson T, et al: Central nervous system complications of non-Hodgkin's lymphoma: The potential role for prophylactic therapy. Am J Med66:435-443, 1979[Medline]
3.
Bunn PA Jr, Schein PS, Banks PM, et al: Central nervous system complications in patients with diffuse histiocytic and undifferentiated lymphoma: Leukemia revisited. Blood47:3-10, 1976 4. Levitt LJ, Dawson DM, Rosenthal DS, et al: CNS involvement in the non-Hodgkin's lymphomas. Cancer45:545-552, 1980[Medline] 5. Recht L, Straus DJ, Cirrincione C, et al: Central nervous system metastases from non-Hodgkin's lymphoma: Treatment and prophylaxis. Am J Med84:425-435, 1988[Medline]
6.
Litam JP, Cabanillas F, Smith TL, et al: Central nervous system prophylaxis with combined intravenous and intrathecal methotrexate in diffuse lymphoma of aggressive histologic type. Blood54:1249-1257, 1979 7. Mackintosh FR, Colby T, Podolsky W, et al: Central nervous system involvement in non-Hodgkin's lymphoma: An analysis of 105 cases. Cancer49:586-595, 1982[Medline] 8. Liang R, Woo EKW, Yu Y-L, et al: Central nervous system involvement in non-Hodgkin's lymphoma. Eur J Cancer Clin Oncol 25:703-710 1989 9. Mead GM, Kennedy P, Smith JL, et al: Involvement of the central nervous system by non-Hodgkin's lymphoma in adults: A review of 36 cases. Q J Med231:699-714, 1986 10. Bokstein F, Lossoa A, Siegal T: Leptomeningeal metastases from solid tumors. Cancer82:1756-1763, 1998[Medline]
11.
Enting RH, Esselink RAJ, Portegies P: Lymphomatous meningitis in AIDS-related systemic non-Hodgkin's lymphoma: A report of eight cases. J Neurol Neurosurg Psychiatry57:150-153, 1994
12.
Graham FL, Whitmore GF: The effect of 1-beta-D-arabinofuranosyl-cytosine on growth, viability, and DNA synthesis of mouse L-cells. Cancer Res30:2627-2635, 1970 13. Zimm S, Collins JM, Miser J, et al: Cytosine arabinoside cerebrospinal fluid kinetics. Clin Pharmacol Ther35:826-830, 1984[Medline]
14.
Kim S, Chatelut E, Kim JC, et al: Extended CSF cytarabine exposure following intrathecal administration of DTC 101. J Clin Oncol11:2186-2193, 1993 15. Kohn FR, Malkmus SA, Brownson EA, et al: Fate of the predominant phospholipid component of DepoFoam drug delivery matrix after intrathecal administration of sustained-release encapsulated cytarabine in rats. Drug Delivery5:143-151, 1998
16.
Chamberlain MC, Kormanik PA: Non-AIDS-related lymphomatous meningitis: Combined modality therapy. Neurology49:1728-1731, 1997
17.
Chamberlain MC, Dirr L: Involved field radiotherapy and intra-Ommaya methotrexate/ara-C in patients with AIDS-related lymphomatous meningitis. J Clin Oncol11:1978-1984, 1993 18. Ziegler JL, Bluming AZ: Intrathecal chemotherapy in Burkitt's lymphoma. Br Med J3:508-512, 1971 Submitted January 11, 1999; accepted May 27, 1999.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
80,000 and WBCs 
