A phase I study of high-dose tamoxifen for the treatment of refractory malignant gliomas of childhood.
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 safety 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 at 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 ease 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.
Pollack
I F
IF
Departments of Neurosurgery, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. ian_pollack@poplar.chp.edu
DaRosso
R C
RC
Robertson
P L
PL
Jakacki
R L
RL
Mirro
J R
JR
Blatt
J
J
Nicholson
S
S
Packer
R J
RJ
Allen
J C
JC
Cisneros
A
A
Jordan
V C
VC
D000284:Administration, Oral; D000293:Adolescent; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000009:adverse effects*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008297:Male; D016019:Survival Analysis; D013629:Tamoxifen / Q000008:administration & dosage / Q000009:adverse effects*; D013997:Time Factors
D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen