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In Reply

Texas Children's Cancer Center/Baylor College of Medicine, Houston, TX

Frank Balis

Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD

David Poplack

Texas Children's Cancer Center/Baylor College of Medicine, Houston, TX

We appreciate the interest Dr Chamberlain showed in our article,¹ and we agree that the schedule and route of mafosfamide used in this trial may be inconvenient. This trial was conducted by institutions with a specific interest in developing new therapies for the treatment of neoplastic meningitis. Approximately 20% of the patients in this trial were older than 18 years and were treated without difficulty at a large academic neuro-oncology program for adults. Our study demonstrated that mafosfamide can be safely and feasibly delivered as a 20-minute infusion, alternating between ventricular and lumbar administration in this setting. The initial development of novel therapies, such as intrathecal mafosfamide, may require expertise and resources that are not generally available in the community setting in order to maximize the information gained and evaluate the safety and efficacy under optimal conditions. Later stages of drug development are more likely to include consideration of whether and how the therapy can be delivered in a less highly specialized setting.

We believe that Dr Chamberlain's conclusion regarding the applicability of intrathecal mafosfamide to adults and adult tumor histologies may be premature. This phase I trial was not designed to determine whether mafosfamide was effective against meningeal malignancy in either children or adults. The dose escalation design in a phase I trial means that many patients receive less than the optimal dose, and there are too few patients with any one diagnosis to draw conclusions about the activity of the agent. Nevertheless, we found it encouraging that several patients received intrathecal mafosfamide for a prolonged period of time, despite prior extensive therapy.

The extent of disease and tumor response to treatment in the meninges are difficult to quantify using CSF cell counts, cytology, and magnetic resonance imaging. Response was not a primary end point of this trial, but disease status was followed closely in these patients to determine whether they were benefiting from the experimental therapy. Only patients who had complete clearing of malignant cells from the CSF were eligible to remain on study after the induction period. However, disease control was experienced for a relatively prolonged period of time in several patients, suggesting that in the phase I setting, it is reasonable to continue therapy in the absence of a complete response. As Dr Chamberlain indicates, there is currently no consensus on the optimal definitions for response or benefit in patients with this condition. New biomarkers are needed to accurately and sensitively assess meningeal tumor burden and response to treatment.

In conclusion, we agree with Dr Chamberlain that the development of new intrathecal agents for the treatment of neoplastic meningitis is extremely challenging, but essential considering the limited number of agents currently available and the increasing frequency of meningeal recurrences in patients with solid tumors. Further testing of intrathecal mafosfamide in the context of a clinical trial will be necessary to establish whether it has a role in the treatment of neoplastic meningitis.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCE

1. Blaney SM, Balis FM, Berg S, et al: Intrathecal mafosfamide: A preclinical pharmacology and phase I trial. J Clin Oncol 23:1555-1563, 2005[Abstract/Free Full Text]

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Related Correspondence

• Mafosfamide: A New Intra-CSF Chemotherapy?
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