This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Barista, I. Articles by Howell, S. B. Search for Related Content PubMed PubMed Citation Articles by Barista, I. Articles by Howell, S. B. Social Bookmarking                            What's this?

Intrathecal Cytarabine and Bone Marrow Suppression

brahim Barita

Hacettepe University Ankara, Turkey

To the Editor:I read the excellent article by Glantz et al¹ with great interest. Their study compares the efficacy and safety of a slow-release versus a standard formulation of intrathecal cytarabine (Ara-C) for the treatment of lymphomatous meningitis. They achieved a 71% response rate and a better control of symptoms in the slow-release Ara-C group. Regarding the drug-related adverse events, the authors reported that three of 14 patients in the slow-release Ara-C group had experienced grade 4 neutropenia, which corresponded to 4% of slow-release Ara-C cycles. It was also noted that eight patients in the slow-release Ara-C group were receiving concurrent systemic chemotherapy. Indeed, systemic chemotherapy could be the cause of grade 4 neutropenia; however, slow-release intrathecal Ara-C might also be responsible for this side effect.

The systemic effects of intrathecal chemotherapy have been well described, including leukopenia^2,3 and tumor lysis syndrome.^4,5 The anatomic relationship between the medulla spinalis and the bone marrow, particularly with regard to the vertebral and pelvic compartments, might explain the sensitivity to intrathecal chemotherapy leading to myelosuppression and tumor lysis syndrome.^6,7 Methotrexate is not metabolized in the CSF, and its intrathecal injection provides a slow-release reservoir of methotrexate into the bloodstream with prolonged cytotoxic levels.^5,8 Likewise, cytidine deaminase, which inactivates Ara-C, is lacking in the CSF,⁹ which leads to higher and more prolonged CSF levels of this drug. Being composed of spherical particles and lipids, slow-release Ara-C maintains cytotoxic concentrations in the CSF for more than 14 days.¹⁰ Thus it is likely that this new intrathecal compound is a potential offender for the unexpected bone marrow suppression episodes.

REFERENCES

1. Glantz MJ, LaFolette S, Jaeckle KA, et al: Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. J Clin Oncol 17:3110-3116, 1999[Abstract/Free Full Text]

2. Fizazi K, Asselain B, Vincent-Salomon A, et al: Meningeal carcinomatosis in patients with breast carcinoma: Clinical features, prognostic factors, and results of a high-dose intrathecal methotrexate regimen. Cancer 77:1315-1323, 1996[Medline]

3. Giannone L, Greco FA, Hainsworth JD: Combination intraventricular chemotherapy for meningeal neoplasia. J Clin Oncol 4:68-73, 1986[Abstract]

4. Simmons ED, Somberg KA: Acute tumor lysis syndrome after intrathecal methotrexate administration. Cancer 67:2062-2065, 1991[Medline]

5. Benekli M, Güllü H, Sava C, et al: Acute tumor lysis syndrome following intrathecal methotrexate. Leuk Lymphoma 22:361-363, 1996[Medline]

6. Greitz D: Cerebrospinal fluid circulation and associated intracranial dynamics: A radiologic investigation using MR imaging and radionuclide cisternography. Acta Radiol 34:1-23, 1993 (suppl 386)

7. Barita , Çelik , Güllü , et al: Intrathecal chemotherapy and bone marrow. Leukemia 11:1392-1393, 1997[Medline]

8. Shapiro WR, Young DR, Mehta BN: Distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med 293:161-166, 1975[Abstract]

9. Ho DHW: Distribution of kinase and deaminase of 1-beta-D arabinofuranosylcytosine in tissues of men and mouse. Cancer Res 33:2816-2820, 1973[Abstract/Free Full Text]

10. Kim S, Chatelut E, Kim JC, et al: Extended CSF cytarabine exposure following intrathecal administration of DTC 101. Oncol 11:2186-2193, 1993

Response

University of California at San Diego La Jolla, CA

In Reply:Dr Barita raises the question of whether intrathecal administration of 50 mg of DepoCyt^TM (cytarabine; Chiron Corp, Emeryville, CA, and Skye Pharma, Inc, San Diego, CA) increases the risk of the development of neutropenia in patients with lymphomatous meningitis receiving concurrent systemic chemotherapy. This slow-release formulation of cytarabine can maintain cytotoxic concentrations in the CSF for more than 14 days in most patients. Barita concludes from this that leakage of cytarabine into the systemic circulation likely accounts for the three episodes of grade 4 neutropenia that were observed in three of the 14 patients receiving DepoCyt reported in our recent article.¹

In the controlled trial of DepoCyt versus free cytarabine for the treatment of lymphomatous meningitis, grade 4 neutropenia was observed on three of 74 cycles in three of the 14 patients receiving this drug. Each patient had only a single episode of neutropenia. The episodes of neutropenia were not unexpected; they were all temporally linked to the administration of systemic chemotherapy at doses commonly associated with severe neutropenia in patients who each had received extensive prior chemotherapy. In one patient with an AIDS-related lymphoma, grade 4 neutropenia was noted on the day of DepoCyt administration 10 days after intravenous (IV) administration of 420 mg of cyclophosphamide, 126 mg of etoposide, and 26 mg of doxorubicin. In a second patient, the neutropenia was discovered 29 days after IV administration of 55 mg of cisplatin, 3.2 g of ifosfamide, and 4.4 g of cytarabine, which was 12 days after the last DepoCyt injection. In the third patient, neutropenia developed on the day of DepoCyt administration, which was 9 days after IV injection of 85 mg of doxorubicin, 1.3 g of cyclophosphamide, and 2.4 mg of vincristine. Neutropenia was not observed in any patient not receiving systemic chemotherapy. It is also noteworthy that, when considering all patients thus far treated with DepoCyt or free cytarabine in the five clinical trials completed to date, neutropenia occurred on 7% of cycles in patients treated with DepoCyt, whereas it occurred on 10% of cycles in patients receiving standard intrathecal therapy with cytarabine 50 mg twice a week. Thus, despite the slow release of cytarabine from DepoCyt, the risk of significant systemic toxicity is no greater.

As Barita notes, systemic leakage of methotrexate after intrathecal administration has been reported to contribute to the development of neutropenia. However, the pharmacokinetics of intrathecally administered cytarabine and methotrexate are quite different. After exiting the CSF and entering the systemic circulation, cytarabine has a plasma half-life of only 17 minutes,² whereas methotrexate has a terminal half-life of 6 to 20 hours.³ Thus, after intraventricular administration of methotrexate at a dose of 6.25 mg/m², systemic levels of up to 0.1 µmol/L were readily measured.⁴ However, after intrathecal administration of even 75 mg of DepoCyt, no measurable amounts of either cytarabine or its principal metabolite uracil arabinoside were detectable in the plasma.⁵ Given the experience with continuous IV infusions of cytarabine for up to 7 days,⁶ it is unlikely that a total dose of 50 mg of cytarabine would have a measurable effect on neutrophil count, even if administered directly into the systemic circulation over 7 days. Thus it is quite unlikely that intrathecal administration of DepoCyt poses a significant risk of medically serious neutropenia, even in patients receiving concurrent systemic chemotherapy.

REFERENCES

1. Glantz M, LaFollette S, Jaeckle K, et al: Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. J Clin Oncol 17:3110-3116, 1999

2. Lopez JA, Nassif E, Vannicola P, et al: Central nervous system pharmacokinetics of high-dose cytosine arabinoside. J Neurooncol 3:119-124, 1985[Medline]

3. Bertino JR, Romanini A: Folate antagonists, in Holland JF, Frei E III, Bast RC Jr, et al (eds): Cancer Medicine (ed 3). Philadelphia, PA,Lea & Febiger, 1993, pp 698-711

4. Shapiro WR, Young DF, Mehta BM: Methotrexate distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med 293:161-166, 1975

5. Chamberlain MC, Khatibi S, Kim JC, et al: Treatment of leptomeningeal metastasis with intraventricular administration of depot cytarabine (DTC 101): A phase I study. Arch Neurol 50:261-264, 1993[Abstract/Free Full Text]

6. Frei E III, Bickers JN, Hewlett JS, et al: Dose schedule and antitumor studies of arabinosyl cytosine (NSC 63878). Cancer Res 29:1325-1332, 1969[Abstract/Free Full Text]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Barista, I. Articles by Howell, S. B. Search for Related Content PubMed PubMed Citation Articles by Barista, I. Articles by Howell, S. B. Social Bookmarking                            What's this?