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Mafosfamide: A New Intra-CSF Chemotherapy?

H. Lee Moffitt Cancer Center, Tampa, FL

To the Editor:

Dr Blaney and her colleagues are to be congratulated for their article detailing the pharmacokinetics (PK) of a novel chemotherapeutic, mafosfamide (MAFOS) administered intra-CSF.¹ Several issues regarding the article are relevant and warrant discussion.

The article is primarily a pediatric study of MAFOS PK and leptomeningeal metastases (LM), secondary to either acute lymphocytic leukemia (ALL) or primitive neuroectodermal tumors (PNETs). Additionally, six of seven patients with a partial response were seen in patients with ALL, which is a disease responsive to intra-CSF chemotherapy. No responders were seen among patients with solid tumors, represented primarily by children with PNETs. The poor response of this subset may be a reflection of previous alkylator-based therapy and concomitant expansion of O⁶-alkylguanine alkyltransferase-positive clonogens.² As such, the applicability to adults and adult tumor histologies seems limited.

A practical issue is the method of intra-CSF administration. MAFOS requires twice-per-week 20-minute intra-CSF infusion to mitigate acute infusion-related headache that limited MAFOS dose escalation beyond 5 mg. Further, the short half-life of MAFOS (70 minutes), results in subtherapeutic lumbar levels when administered intraventricularly. As a consequence, patients with LM require alternating lumbar and ventricular MAFOS infusions to ensure neuraxis treatment. Both of these issues we believe limit the applicability to busy adult oncology practices.

Another aspect of the study that appears idiosyncratic is the criteria utilized regarding assessment of outcome. The construct of a partial response to intra-CSF chemotherapy is unusual in that quantitative CSF cytology is rarely performed, and never in the context of a clinical trial.³ As a result, cytologic response is customarily referred to as either complete disappearance (complete response) or persistent tumor in CSF (lack of response).^4,5 Evaluating outcome based on a partial response therefore seems problematic. Further, partial response was also defined by a 50% or greater decrement in disease defined neurographically. Most instances of neurographic disease consistent with LM represent bulky disease not responsive to CSF-based regional chemotherapy, and consequently, are treated with either involved-field radiotherapy or systemic chemotherapy.⁶ Similarly, stable disease was defined by no quantitative change in CSF cytology. In other randomized trials of LM, patients with persistently positive CSF cytology following induction therapy would be considered nonresponsive and offered alternative therapy.

These comments are not meant to diminish the results of this elegant study, notable for determination of in vitro cytotoxicity, nonhuman primate studies, and pharmacokinetics of MAFOS; rather the comments reflect the difficulty encountered in treating patients with LM and the lack of standardization regarding treatment.

Author's Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

REFERENCES

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]

2. Russack V, Kim S, Chamberlain MC: Quantitative CSF cytology in patients receiving intra-cavitary chemotherapy. Ann Neurol 34:108-112, 1993[CrossRef][Medline]

3. Herman JG, Baylin SB: Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349:2042-2054, 2003[Free Full Text]

4. Glantz M, Jaeckle K, Chamberlain MC, et al: A randomized trial comparing intrathecal sustained-release ara-C (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res 11:3394-3402, 1999

5. Glantz M, Jaeckle KA, Chamberlain MC, et al: A randomized trial of a slow-release formulation of cytarabine for the treatment of lymphomatous meningitis. J Clin Oncol 17:3110-3116, 1999[Abstract/Free Full Text]

6. Chamberlain MC, Kormanik P: Prognostic significance of co-existent bulky metastatic central nervous system disease in patients with leptomeningeal metastases. Arch Neurol 54:1364-1368, 1997[Abstract/Free Full Text]

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  Susan M. Blaney, Stacey L. Berg, Frank Balis, and David Poplack
  JCO 2005 23: 7749 [Full Text]

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 Chamberlain, M. C. Search for Related Content PubMed PubMed Citation Articles by Chamberlain, M. C. Related Articles Related Reply Social Bookmarking                            What's this?