A phase I study of high-dose tamoxifen for the treatment of refractory malignant gliomas of childhood

Ian F. Pollack, Robert C. Darosso, Patricia L. Robertson, Regina L. Jakacki, Joseph R. Mirro, Julie Blatt, Stacy Nicholson, Roger J. Packer, Jeffrey C. Allen, Angela Cisneros, V. Craig Jordan

Research output: Contribution to journalArticle

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Abstract

Recent studies have indicated that the proliferation of malignant gliomas is in part dependent on excessive activation of protein kinase C (PKC)-mediated pathways. Conversely, inhibiting PKC may provide a novel approach for blocking glioma growth. The antiestrogen tamoxifen, a moderately potent PKC inhibitor, has been shown in vitro to block the proliferation of malignant glioma cell lines at concentrations several-fold higher than those typically attained during the treatment of breast cancer; such serum concentrations may be achieved with doses > 40 mg/m2 b.i.d. The safely and efficacy of these high doses for producing disease control in patients with malignant gliomas has recently been noted anecdotally, although a rigorous study of this agent has been lacking. To address this issue, we examined the safety and efficacy of high-dose tamoxifen in a series of children with malignant gliomas that had progressed after conventional therapy. An initial group was treated with 60 mg/m2 p.o. b.i.d. and a second group with 100 mg/m2 b.i.d. Steady-state serum tamoxifen and metabolite levels were measured in most patients. Toxicity with the regimen was minimal; two patients treated at the higher dose required reduction to the lower dose because of asymptomatic prolongation of the QT interval on an electrocardiogram. Although none of the patients exhibited clear-cut tumor regression, 4 of 14 patients had stabilization of previously progressive disease for al least 3 months; the longest survivor lived for 17 months after beginning tamoxifen. The moderate efficacy of this agent in otherwise end- stage disease coupled with its low toxicity and the relative case of oral administration provides a rationale for proceeding with larger studies of this agent in patients with malignant gliomas, possibly as a means for potentiating the effects of conventional chemotherapeutic agents, which to date have shown limited efficacy in the treatment of these tumors.

Original languageEnglish (US)
Pages (from-to)1109-1115
Number of pages7
JournalClinical Cancer Research
Volume3
Issue number7
StatePublished - Jul 1997
Externally publishedYes

Fingerprint

Tamoxifen
Glioma
Protein Kinase C
Therapeutics
Estrogen Receptor Modulators
Protein C Inhibitor
Proxy
Protein Kinase Inhibitors
Serum
Oral Administration
Survivors
Neoplasms
Electrocardiography
Breast Neoplasms
Safety
Cell Line
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Pollack, I. F., Darosso, R. C., Robertson, P. L., Jakacki, R. L., Mirro, J. R., Blatt, J., ... Jordan, V. C. (1997). A phase I study of high-dose tamoxifen for the treatment of refractory malignant gliomas of childhood. Clinical Cancer Research, 3(7), 1109-1115.

A phase I study of high-dose tamoxifen for the treatment of refractory malignant gliomas of childhood. / Pollack, Ian F.; Darosso, Robert C.; Robertson, Patricia L.; Jakacki, Regina L.; Mirro, Joseph R.; Blatt, Julie; Nicholson, Stacy; Packer, Roger J.; Allen, Jeffrey C.; Cisneros, Angela; Jordan, V. Craig.

In: Clinical Cancer Research, Vol. 3, No. 7, 07.1997, p. 1109-1115.

Research output: Contribution to journalArticle

Pollack, IF, Darosso, RC, Robertson, PL, Jakacki, RL, Mirro, JR, Blatt, J, Nicholson, S, Packer, RJ, Allen, JC, Cisneros, A & Jordan, VC 1997, 'A phase I study of high-dose tamoxifen for the treatment of refractory malignant gliomas of childhood', Clinical Cancer Research, vol. 3, no. 7, pp. 1109-1115.
Pollack IF, Darosso RC, Robertson PL, Jakacki RL, Mirro JR, Blatt J et al. A phase I study of high-dose tamoxifen for the treatment of refractory malignant gliomas of childhood. Clinical Cancer Research. 1997 Jul;3(7):1109-1115.
Pollack, Ian F. ; Darosso, Robert C. ; Robertson, Patricia L. ; Jakacki, Regina L. ; Mirro, Joseph R. ; Blatt, Julie ; Nicholson, Stacy ; Packer, Roger J. ; Allen, Jeffrey C. ; Cisneros, Angela ; Jordan, V. Craig. / A phase I study of high-dose tamoxifen for the treatment of refractory malignant gliomas of childhood. In: Clinical Cancer Research. 1997 ; Vol. 3, No. 7. pp. 1109-1115.
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