Intrathecal Sustained-Release Cytarabine (Depocyt) for Patients with Neoplastic Meningitis
February 1, 2000 4 minutes read
Intrathecal Sustained-Release Cytarabine (Depocyt) for Patients with Neoplastic Meningitis
ABSTRACT & COMMENTARY
Synopsis: A sustained release formulation of cytarabine (DepoCyt) has been shown to maintain cytotoxic drug concentration in the CSF for more than 14 days after a single 50 mg injection.
Source: Glantz MJ, et al. Clin Cancer Res 1999; 5:3394-3402.
Carcinomatous meningitis can occur in approximately 5-8% of patients with advanced solid tumors. Primary solid tumors that have been associated with this disease process include breast cancer, lung cancer, and melanoma. The entire neuraxis can be seated, and signs and symptoms can involve either the brain, cranial nerves, or spinal nerves. The "gold standard" for diagnosis requires demonstration of malignant cells in the CSF. In patients with subsequent demonstration of carcinomatous meningitis, 50% of patients will have a positive cytology following the first spinal tap and by the third spinal tap more than 90% of patients will have positive CSF cytology.
Treatment for patients with carcinomatous meningitis can include surgery, radiotherapy, and chemotherapy. Surgical intervention may be needed for patients with obstructive hydrocephalus and for placement of an Ommaya reservoir for intrathecal chemotherapy. Radiotherapy can be administered to focal sites of disease causing significant symptoms. In addition, cranial or cranial spinal/radiation can be administered. However, the toxicity of cranial/spinal radiation has greatly limited its use.
The primary treatment intervention for patients with carcinomatous meningitis has been intrathecal chemotherapy. The administration of intrathecal methotrexate (10 mg twice per week) or cytosine arabinoside (90 mg/week), is frequently used treatment schedules. These frequent treatment administrations can be difficult for the patients. Thus, improvements in treatment scheduling would be expected to have clinical benefits.
Several potential prognostic factors have been identified for patients with meningeal carcinomatosis. These prognostic factors include age, performance status, tumor type, presence of cranial nerve deficits, and duration of carcinomatous meningitis. In addition, the status of the systemic malignancy is an important factor for these patients.
The formulation of sustained released cytarabine (DepoCyt) for intrathecal administration has potential pharmacologic as well as practical advantages. The requirement for treatment administration every two weeks, compared with twice weekly, would be a practical advantage for patients. In addition, exposure of neoplastic cells to a sustained release preparation of a cell cycle phase-specific agent would have potential therapeutic benefit. Thus, a comparative clinical study of a sustained release preparation of cytarabine with a standard intrathecal preparation of methotrexate addressed a reasonable clinical question.
Comment by Mark R. Albertini, MD
The clinical study reported by Glantz and colleagues supports administration of intrathecal sustained-released cytarabine (DepoCyt) for patients with neoplastic meningitis from solid tumors. Glantz et al report a response rate comparable to that of intrathecal methotrexate and describe an improved time to neurologic progression. The described prognostic factors were well balanced between treatment groups. The toxicity profiles for each treatment group appear comparable. An appropriate intent-to-treat model was used for the primary analysis end points.
Several aspects of the study require some commentary. While nine of the DepoCyt treated patients received all six planned cycles of therapy, none of the 30 methotrexate treated patients received all of the planned cycles of therapy. The reason for this difference in administered treatment was not clearly identified and may relate to the short median time to neurologic progression in the methotrexate treatment group.
The baseline characteristics of the patients were well identified. All patients were required to have confirmation of malignant cells in the CSF for entry into this study. In addition, all patients were required to have normal CSF flow as demonstrated by a 99Technetium or 111Indium CSF flow study prior to randomization. In addition, patients with a Karnofsky performance status less than 60% were excluded from this study.
Glantz et al report a well-balanced breakdown of tumor types between both treatment groups. The primary responders in the DepoCyt group were patients with underlying primary brain tumors (5 of the 8 respondents), with additional respondents including patients with breast cancer (2 patients) and other malignancies (1 patient). In contrast, responders in the methotrexate treatment group included patients with primary brain tumor (2 patients), melanoma (1 patient), non-small cell lung cancer (1 patient), and small cell lung cancer (2 patients). It is impossible to make disease-specific conclusions with the small number of patients in each of the various disease subsets.
In conclusion, Glantz et al report an interesting study evaluating a sustained release DepoCyt formulation for intrathecal administration in patients with neoplastic meningitis from solid tumors. Glantz et al’s conclusion that DepoCyt provides longer progression-free survival needs to be interpreted cautiously for an individual patient due to the small number of patients in each of the histologic entities in this study. However, DepoCyt had comparable safety and a more convenient dosing schedule than methotrexate for a disease process with an ominous prognosis. Thus, DepoCyt represents a reasonable treatment consideration for patients with neoplastic meningitis. Further advances for the treatment of patients with this diagnosis are clearly needed.
References
1. Brain Metastases and Carcinomatous Meningitis. Carcinomatous Meningitis. In: Abeloff, Armitage, Lichter, Niederhuber, eds. Clinical Oncology. 2nd ed.New York, NY: Churchill Livingstone Publishing; 2000:829-832.
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Which of the following statements about intrathecal sustained-release Cytarabine (DepoCyt) for the treatment of patients with neoplastic meningitis from solid tumors is true?
a. Response rates were significantly improved with intrathecal sustained-release Cytarabine in comparison with intrathecal methotrexate.
b. Median survival was significantly improved with sustained-release Cytarabine in comparison with intrathecal methotrexate.
c. The median time to neurologic progression was significantly extended in patients receiving intrathecal sustained-release Cytarabine in comparison with intrathecal methotrexate.
d. Intrathecal sustained-release Cytarabine had fewer adverse advents in comparison with intrathecal methotrexate.
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