A Phase 2 Trial of Neoadjuvant Temozolomide Followed by Hypofractionated Accelerated Radiation Therapy With Concurrent and Adjuvant Temozolomide for Patients With Glioblastoma

Int J Radiat Oncol Biol Phys. 2017 Mar 1;97(3):487-494. doi: 10.1016/j.ijrobp.2016.11.006. Epub 2016 Nov 15.

Abstract

Purpose: We performed a phase 2 trial of neoadjuvant temozolomide (TMZ), followed by hypofractionated accelerated radiation therapy (HART) with concurrent TMZ, and adjuvant TMZ in patients with newly diagnosed glioblastoma to determine whether neoadjuvant TMZ would safely improve outcomes in this group of patients prior to subsequent cytotoxic therapy.

Methods and materials: Adult patients with newly diagnosed glioblastoma and a Karnofsky Performance Status >60 were eligible. Neoadjuvant TMZ administration started 2 to 3 weeks from surgery at a daily dose of 75 mg/m2 for 2 weeks prior to delivery of HART (60 Gy in 20 daily fractions) with concurrent and adjuvant TMZ. The primary endpoints were feasibility and toxicity. The secondary endpoints included overall survival (OS) and progression-free survival.

Results: Fifty patients were accrued. The median follow-up period was 44.0 months for patients at risk and 22.3 months for all 50 patients. Except for 1 patient in whom infection developed and another patient with progression during HART, all patients completed protocol therapy as planned. The median OS and progression-free survival were 22.3 months (95% confidence interval, 14.6-42.7 months) and 13.7 months (95% confidence interval, 8.0-33.3 months), respectively. The 4-year OS rates were 30.4% for the entire cohort and 53.3% and 14.0% for patients with methylated (n=21) and unmethylated (n=27) MGMT gene promoter tumors, respectively. One patient had grade 5 pancytopenia during HART, and another patient had transient grade 4 hepatotoxicity. A second surgical procedure was performed in 13 patients: 2 had intracranial infection, 3 had recurrences, 4 had recurrences and radiation-induced damage, and 4 had only radiation-induced damage.

Conclusions: This novel approach of neoadjuvant TMZ is associated with an encouraging favorable long-term survival with acceptable toxicity. A future comparative trial of the efficacy of this regimen is warranted.

Trial registration: ClinicalTrials.gov NCT01702610.

Publication types

  • Clinical Trial, Phase II

MeSH terms

  • Adult
  • Antineoplastic Agents, Alkylating / therapeutic use*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / therapy*
  • Chemoradiotherapy / adverse effects
  • Chemoradiotherapy / methods*
  • Chemotherapy, Adjuvant / adverse effects
  • Chemotherapy, Adjuvant / methods
  • DNA Methylation
  • DNA Modification Methylases / genetics
  • DNA Repair Enzymes / genetics
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / therapeutic use
  • Disease-Free Survival
  • Drug Administration Schedule
  • Female
  • Follow-Up Studies
  • Glioblastoma / genetics
  • Glioblastoma / therapy*
  • Humans
  • Karnofsky Performance Status
  • Male
  • Middle Aged
  • Neoadjuvant Therapy / methods
  • Pancytopenia / etiology
  • Prospective Studies
  • Radiation Dose Hypofractionation
  • Reoperation
  • Temozolomide
  • Time Factors
  • Treatment Failure
  • Treatment Outcome
  • Tumor Suppressor Proteins / genetics

Substances

  • Antineoplastic Agents, Alkylating
  • Tumor Suppressor Proteins
  • Dacarbazine
  • DNA Modification Methylases
  • MGMT protein, human
  • DNA Repair Enzymes
  • Temozolomide

Associated data

  • ClinicalTrials.gov/NCT01702610