Ventriculolumbar perfusion chemotherapy for the treatment of leptomeningeal carcinomatosis: a phase I study with pharmacokinetic data.

OBJECTIVES

To define the maximum tolerated dose, toxicities, and pharmacokinetics of the ventriculolumbar perfusion (VLP) chemotherapy for leptomeningeal carcinomatosis, according to different modes of administration, perfusion rate, and daily methotrexate (MTX) dose.

METHODS

For bolus injection modes, a designated MTX dose was given every 12 hours, for 3 consecutive days, with artificial cerebrospinal fluid perfusion. The starting daily MTX dose was 40 mg for 40 mL/h perfusion, and 24 mg for 20 mL/h, respectively. Although in continuous infusion modes, MTX premixed in artificial cerebrospinal fluid was infused for 3 consecutive days. The dose-limiting toxicity (DLT) was defined to be equal to or more than grade 3 side effects, as per the Common Terminology Criteria for Adverse Events.

RESULTS

The perfusion rate of 40 mL/h provoked perfusion-related symptoms, such as nausea/vomiting and insomnia, and revealed DLTs including encephalopathy in more than 1/3 of patients in both administration modes when the daily MTX dose of 40 mg was given. The schedule of 20 mL/h perfusion with the daily MTX dose of 24 mg showed milder perfusion-related side effects and provoked no DLT in both administration modes. The relationship between the peak MTX concentration and encephalopathy was not statistically significant. Of 19 patients with increased intracranial pressure, the intracranial pressure was normalized in 14 patients after VLP therapy.

CONCLUSIONS

This study disclosed the VLP chemotherapy with a perfusion rate of 20 mL/h and the daily MTX dose of 24 mg could be adopted for future study.