A Phase I Clinical Trial Assessing Temozolamide and Tamoxifen with Concomitant Radiotherapy for the Treatment of High-Grade Gliomas

Reviewer: Chika Madu, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 18, 2005

Presenter: T.W. Flannery
Presenter's Affiliation: Radiation Oncology, University of Maryland, Baltimore, MD
Type of Session: Scientific


One of the many recent advances in the management of high grade gliomas includes the slight survival advantage seen with the use of concurrent temozolamide and radiation for glioblastoma multiforme (GBM). Pre-clinical data have also shown that protein kinase C (PKC) mediated pathways may play a role in the proliferation of high-grade gliomas. Through estrogen receptor independent effects, tamoxifen inhibits PKC in vitro. Since tamoxifen and its metabolite have been shown to cross the blood brain barrier to sufficient intratumoral levels, this Phase I study was designed to determine the maximum tolerated dose (MTD) of tamoxifen when given with concurrent chemo-radiotherapy.

Materials and Methods

  • 17 patients diagnosed with high grade glioma, (2 patients with WHO grade III, and 15 with WHO grade IV) were enrolled in 4 cohorts from 7/01-6/03
  • Inclusion criteria were as follows: histological diagnosis, age >18, KPS of at least 60, life expectancy > 3  months, and no prior chemotherapy or brain radiation
  • Median age was 51 years (range 18-78 years)
  • 2 patients had gross total resection, 9 patients had sub-total resection, and 6 patients had biopsy only
  • All patients received tamoxifen at incremental doses twice daily concurrent with temozolamide (75mg/m2) and radiation (60Gy/2Gy fractions, to partial brain)
  • Tamoxifen was started at 50mg/m2 divided twice a day, then escalated in 25mg/m2 increments if there were no dose limiting toxicities (DLT) in ≥3 patients
  • The MTD was exceeded if a DLT was shown in ≥ 2 patients within any cohort
  • DLT was according to CTC version 2.0, and all patients received weekly electrocardiograms, mini mental status examinations (MMSE), and labs


  • In cohort 4, one patient was excluded due to QT prolongation, one patient had grade 4 thrombocytopenia, and another had deep venous thrombosis (DVT) at 125mg/m2 of tamoxifen
  • Other Grade 1-2 toxicities included fatigue, skin reactions, headache, nausea, and hot flashes
  • 12/17 patients completed all chemo-radiotherapy. There were 2 mortalities
  • The MTD was then 100mg/m2 which was the last dose level prior to the grade 3-4 DLT
  • Median survival was 15.5 months, with 4 patients surviving beyond 30 months
  • Three patients are still alive at 31.1, 42.9, and 45.9 months
  • 2 year overall survival was 35%

Author's Conclusions

  • When given concurrently with radiation and temozolamide, the MTD for tamoxifen was 100mg/m2/day
  • There is encouraging survival seen in this group of patients
  • Tamoxifen may improve treatment response in high-grade glioma

Clinical/Scientific Implications

This is a very interesting study looking at the possibility ofimproving treatment responses by adding tamoxifen to the standard regimen of temozolamide and radiation for high grade gliomas. The outcome for patients with high grade glioma, albeit improved over the years, continues to be dismal. Although this study is still in the early phases, the results do look promising. However, tamoxifen does have side effects such as thromboembolism, stroke, thrombocytopenia, and hot flashes.  A phase II study should be performed to further evaluate this regimen.