title: Phase I clinical trial assessing temozolomide and tamoxifen with concomitant radiotherapy for treatment of high-grade glioma.
abstract: OBJECTIVE
  The new standard treatment of glioblastoma multiforme is concurrent radiotherapy (RT) and temozolomide. The proliferation of high-grade gliomas might be partly dependent on protein kinase C-mediated pathways. Tamoxifen has been shown in vitro to inhibit protein kinase C through estrogen receptor-independent antineoplastic effects. This Phase I trial was designed to determine the maximal tolerated dose (MTD) of tamoxifen when given with temozolomide and concurrent RT to patients with high-grade gliomas.
  
  
  METHODS
  A total of 17 consecutive patients in four cohorts with World Health Organization Grade 3 (n = 2) and 4 (n = 15) gliomas were given tamoxifen twice daily during 6 weeks of concurrent RT and temozolomide. Eligibility included histologic diagnosis, age >18 years old, Karnofsky performance status ≥ 60, and no previous brain RT or chemotherapy. The starting dose was 50 mg/m(2) divided twice daily. If no dose-limiting toxicities (DLTs) occurred in 3 patients, the dose was escalated in 25-mg/m(2) increments until the MTD was reached. When ≥ 2 patients within a cohort experienced a DLT, the MTD had been exceeded. Temozolomide was given with RT at 75 mg/m(2). A dose of 60 Gy in 2 Gy/d fractions to a partial brain field was delivered.
  
  
  RESULTS
  A total of 6 patients in Cohort 4 had received tamoxifen at 125 mg/m(2). One patient was excluded, and the fourth patient developed Grade 4 thrombocytopenia (DLT). Thus, 3 more patients needed to be enrolled. A deep venous thrombosis (DLT) occurred in the sixth patient. Thus, the MTD was 100 mg/m(2).
  
  
  CONCLUSIONS
  The MTD of tamoxifen was 100 mg/m(2) when given concurrently with temozolomide 75 mg/m(2) and RT. Tamoxifen might have a role in the initial treatment of high-grade gliomas and should be studied in future Phase II trials building on the newly established platform of concurrent chemoradiotherapy.
authors.affiliation: Department of Radiation Oncology, University of Washington, Seattle, WA 98195-6043, USA. Shilpenp@uw.edu
authors.forename: Shilpen
authors.initials: S
authors.lastname: Patel
authors.forename: Steven
authors.initials: S
authors.lastname: DiBiase
authors.forename: Barry
authors.initials: B
authors.lastname: Meisenberg
authors.forename: Todd
authors.initials: T
authors.lastname: Flannery
authors.forename: Ashish
authors.initials: A
authors.lastname: Patel
authors.forename: Anil
authors.initials: A
authors.lastname: Dhople
authors.forename: Sally
authors.initials: S
authors.lastname: Cheston
authors.forename: Pradip
authors.initials: P
authors.lastname: Amin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001932:Brain Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy / Q000379:methods*; D015331:Cohort Studies; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D004334:Drug Administration Schedule; D005260:Female; D005909:Glioblastoma / Q000401:mortality / Q000473:pathology / Q000628:therapy; D005910:Glioma / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D006801:Humans; D017567:Karnofsky Performance Status; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D015996:Survival Rate; D013629:Tamoxifen / Q000008:administration & dosage / Q000009:adverse effects; D000077204:Temozolomide; D013921:Thrombocytopenia / Q000209:etiology; D020246:Venous Thrombosis / Q000209:etiology; D055815:Young Adult
chemical_list: D013629:Tamoxifen; D003606:Dacarbazine; D011493:Protein Kinase C; D000077204:Temozolomide