Intrathecal depot cytarabine therapy: a welcome addition to a limited armamentarium.

The LMD of a systemic malignancy remains one of the greatest treatment challenges in cancer medicine (1). Few patients with this complication survive for more than a few months, and this outcome has not changed substantially over the past 20–30 years, despite the progress made in controlling cancer at most other sites in the body. Thus, any advance in the treatment of LMD, especially a modality shown to be effective in a randomized, controlled trial, is truly welcome. Such is the case for the IT SR ara-C described by Glantz et al. (2) in this issue of Clinical Cancer Research. The ara-C used by these investigators was encapsulated in a multivesicular liposome preparation named DepoFoam, and the product is known as DTC-101 and DepoCyt (3, 4). This encapsulation of the drug in lipid drastically changes the pharmacokinetics of the free ara-C released by IT SR ara-C in CSF, such that the mean elimination t1/2 of the depot formulation of free ara-C in CSF is 130–277 h (5), versus 3.4 h for native ara-C (Fig. 1; Ref. 6). Furthermore, the cytotoxic concentrations of the SR formulation of the ara-C in CSF are maintained for as long as 14 days or more, depending on the target cell threshold concentration that is cytotoxic. For human lymphoblasts, this concentration is generally thought to be 5 mM, such that the threshold for native ara-C is exceeded for only 1 day or so (Fig. 1). Solid tumors such as carcinoma are thought to have a higher threshold, perhaps 1 or 2 logs higher, but this has not been well characterized. For IT therapy, MTX has been regarded as a better drug than ara-C, in part because it provides a longer exposure in the CSF and penetrates more deeply into the meninges and CNS parenchyma. Specifically, laboratory studies have shown that ara-C diffuses only a few millimeters into the brain parenchyma, regardless of the time or concentration of ara-C in CSF (7). MTX, on the other hand, penetrates more deeply (as a function of the distance from the ependyma), and the depth increases with higher CSF concentrations and longer exposures to the drug in the CSF. Prolonged exposure to cytocidal concentrations of antimetabolites such as MTX and ara-C often results in cell kill in patients with LMD, whereas a short exposure to the same concentrations does not. However, the repeated intra-CSF administrations necessary to accomplish this obviously pose a difficulty, especially when lumbar punctures are required to deliver the agent. To permit repeated intra-CSF administration without the need for repeated lumbar punctures, an Ommaya reservoir is usually implanted with the tip of the cannula inserted into a lateral. However, this requires anesthesia, surgery, and postoperative recovery, and it also risks CNS infection. Nonetheless, this approach has been successful in the treatment of meningeal leukemia (8, 9) or can at least be palliative in patients with solid tumors. The leptomeninges and CSF pose a special cytokinetic problem for the oncologist. On one hand, the CSF concentrations of any agent are much higher after intra-CSF injection than are the plasma levels that can be achieved with the systemic administration of much higher doses of the drug. For example, to match the CSF concentration achieved by an IT dose of 12 mg, the i.v. dosage of MTX must be 33,600 mg/m over 24 h, and even then the peak CSF concentrations are a log or more higher with the IT dose (10). In addition, the removal of agents such as MTX and ara-C from the CSF is much slower than that from the systemic compartment. Thus, agents that are ineffective against non-CNS tumors after systemic administration may be effective against LMD and tumor cells elsewhere within the CNS after IT administration. For this reason, drugs that show no detectable antineoplastic activity in standard Phase I or II clinical trials may be rejected on the basis of current findings but may actually be effective against human LMD under other testing conditions. An additional problem in the treatment of LMD is that malignant cells within the CSF and meninges proliferate very slowly. Leukemic cells, for example have markedly slower cytokinetics in the CSF and meninges than they do in blood or bone marrow. This has been confirmed by the tritiated uridine labeling index of leukemic cells in bone marrow, blood, and CSF, which was found to be 31.5%, 14.0%, and 1.5%, respectively, and the mitotic index, which was found to be 1.1%, 0.02%, and 0.01%, respectively (11). In another study, CSF blasts were found to have thymidine labeling indices of less than 2%, and both CSF and meningeal leukemic cells had mitotic indices of less than 0.02% (12). In patients with meningeal leukemia, the growth fraction has been estimated on the basis of repeated intraventricular injections of tritiated thymidine via an Ommaya reservoir; after 10 days of continuous exposure to the radiolabeled nucleoside, only 21–55% of the cells in the CSF were labeled (12). These observations indicate that the eradication of LMD in patients with cancer will require extraordinarily long exposures to cytocidal concentrations of the antineoplastic agent, especially if it is a cell cycle active agent. Thus, despite the pharmacological advantage of IT administration of an antineoplastic agent in patients with LMD versus systemic administration, the cytokinetics of LMD can nullify this advantage. Received 8/13/99; accepted 8/18/99. 1 To whom requests for reprints should be addressed, at Division of Pediatrics-87, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 7926603; Fax: (713) 745-1549; E-mail: [email protected]. 2 The abbreviations used are: LMD, leptomeningeal dissemination; CSF, cerebrospinal fluid; MTX, methotrexate; CNS, central nervous system; RR, relative risk; SR, sustained release; IT, intrathecal; ara-C, 1-b-D-arabinofuranosylcytosine, cytarabine. 3349 Vol. 5, 3349–3351, November 1999 Clinical Cancer Research