LONG-TERM SURVIVAL OF PATIENTS WITH GLIOBLASTOMA TREATED WITH RADIOTHERAPY AND LOMUSTINE PLUS TEMOZOLOMIDE

Background

• Glioblastoma is a devastating disease; standard chemoradiotherapy with concomitant and adjuvant temozolomide (TMZ) leads to a median progression-free survival (MPFS) of only 6.9 months and a median overall survival (MOS) of only 14.6 months.
• TMZ combats tumor cells by alkylating and damaging DNA. Unfortunately, the O⁶-methylguanine-DNA methyltransferase (MGMT) enzyme repairs this damage, thereby interfering with the therapeutic effects of chemotherapy. Although methylation of the MGMT promoter may silence this enzyme, many patients have unmethylated MGMT promoters. Thus, improved chemotherapy protocols that extend survival are urgently needed.
• The UKT-03 study, which combined TMZ therapy with lomustine (CCNU), revealed promising survival data, with an MPFS of 9 months and an MOS of 22.6 months. Moreover, 13 of the 31 patients included in this trial were alive at the 2-year follow-up analysis.

Objective

• This study, which was carried out 55 months after the start of the UKT-03 trial, was conducted to evaluate long-term survival in patients with glioblastoma treated with a standard course of TMZ and CCNU (ie, the UKT-03 cohort).
• The study was also designed to assess survival in patients with glioblastoma who were treated with an intensified CCNU/TMZ regimen, and to compare safety and efficacy outcomes with standard doses of chemotherapy.
• Additionally, the study sought to evaluate the impact of MGMT promoter methylation on survival outcomes.

Title/Citation

Glas M, Happold C, Rieger J, et al. Long-term survival or patients with glioblastoma treated with radiotherapy and lomustine plus temozolomide. J Clin Oncol. 2009;27:1257-1261. Epub 2009 Feb 2.

Funding

Authors received compensation and honoraria from Schering-Plough.

Trial design

This was a prospective, non-randomized, non-blinded evaluation conducted at the University of Tuebingen and Mainz Medical Centers in Germany.

Enrollment

This study enrolled 31 patients with glioblastoma who were treated with standard CCNU/TMZ therapy in the UKT-03 trial, as well as 8 patients with glioblastoma who were treated in a pilot group with increased CCNU and TMZ doses.

Inclusion criteria

The study included patients with:

• Histologic diagnosis of glioblastoma
• Age greater than 18 years
• Karnofsky performance score (KPS) of 70 or higher

Exclusion criteria

The study excluded patients who had:

• Surgery more than 21 days prior to enrollment
• Prior radiotherapy or chemotherapy
• Poor performance status
• Alterations in bone marrow reserve, liver function, or renal function

Study groups

• 2 regimens were evaluated:
• Standard therapy: oral CCNU 100 mg/m² on day 1, followed by TMZ 100 mg/m²/day on days 2 through 6 of 6-week courses
• Intense therapy: oral CCNU 110 mg/m² on day 1, followed by TMZ 150 mg/m²/day on days 2 through 6 of 6-week courses
• Radiotherapy was delivered during courses 1 and 2, at a total dose of 60 Gy (in single daily fractions of 2 Gy).

End points

• MOS
• MPFS
• Late toxicity

Statistical analyses

• Survival data were analyzed by the Kaplan-Meier method.
• The impact of MGMT promoter methylation status, dosing intensity, and extent of surgical resection were analyzed with a Cox proportional hazards model.

Baseline characteristics

• The study included 31 (79%) males and 8 (21%) females.
• 14 patients (36%) underwent complete tumor resection, 19 (49%) underwent partial tumor resection, and 4 (19%) had a biopsy only.
• The median age of patients in the standard therapy group was 51 years, whereas the median age of those in the intensified group was 59 years.
• Groups did not differ with respect to KPS.
• 8 of 19 investigated patients in the standard group and 3 of 4 in the intensified group had a methylated MGMT promoter.

End points

MOS:

• Overall, the MOS was 23.1 months. OS was 47.4% at 2 years, 26.4% at 3 years, 18.5% at 4 years, and 15.8% at 5 years.
• MOS was significantly higher in patients who received intensified therapy than in those who received standard therapy (P = .024). The MOS was 22.6 months in the standard cohort; MOS was not yet reached in the intensified cohort at a median follow-up time of 41.5 months.
• Of patients who received standard therapy, 41.9% survived 2 years, 16.9% survived 3 years, and 9.7% survived 4 years. Of those who received intensified therapy, 50% survived for at least 56 months.
• Survival strongly depended on MGMT promoter methylation status. MOS was significantly higher in patients with methylated MGMT promoters than in those with nonmethylated promoters (34.3 months vs 12.5 months; P = .0009). Of those with methylated promoters, 45% survived for 3 years and 36% for 5 years.
• Chemotherapy dose and MGMT promoter methylation status influenced survival, whereas extent of surgical resection did not.

MPFS:

• Overall, the MPFS was 10 months, and ranged from 1 to ≥69 months.
• As a whole, 4 (10.3%) patients have had no disease recurrence at last follow-up (69 months); 2 (25%) of those in the intensified cohort have remained recurrence-free.
• MPFS was significantly higher in patients who received intensified therapy than in those who received standard therapy (26 months vs 9 months; P = .014).
• MPFS was significantly higher in patients with methylated MGMT promoters than in those with nonmethylated promoters (19 months vs 7 months; P = .0064).

Toxicity:

• Acute toxicity was higher in patients who received intensified therapy than in those who received standard therapy.
• Grade 4 myelotoxicity occurred in 4 (57%) patients in the intensified cohort, as compared with 5 (16%) of those in the standard cohort.
• There were no signs of therapy-dependent late neurotoxicity in patients who survived long-term.
• KPS remained stable in patients who survived without disease recurrence, but decreased in 2 patients with recurrent disease.

Conclusions

• The combination of CCNU, TMZ, and radiotherapy is largely effective in patients with newly diagnosed glioblastoma, and may lead to substantial long-term survival.
• CCNU/TMZ dose intensification adds a marked survival benefit, although it also increases toxicity.
• Patients with a nonmethylated MGMT promoter in their tumor may not benefit from CCNU/TMZ chemotherapy at any dose.

Study strengths/ limitations

Strengths:

• Long-term survival was an appropriate end point because it is of utmost importance in oncology patients.
• Chemotherapy doses were appropriately selected based on previous literature indicating that toxicity was acceptable with a 50% higher dose of carmustine and a slightly higher dose of TMZ than that which was used.
• Statistical tests were suitably chosen to evaluate findings.
• Investigators assessed the influence of surgical resection on survival, to ensure that differences between groups were due to chemotherapy and not to surgical excision.

Limitations:

• The study had a small sample size (39 patients overall and only 8 patients in the intensified cohort), which made it difficult to formulate definitive conclusions regarding the efficacy and toxicity of therapy.
• The study excluded patients with a poor performance status, which may have reduced external validity.
• Patients in the intensified therapy cohort were significantly older than those in the standard therapy cohort. Given that age may influence glioblastoma prognosis, this disparity may have affected results.
• Several patients received second resections and multiple salvage therapies, which may have influenced findings.
• Investigators received funding from Schering-Plough, the manufacturer of TMZ. However, it is important to keep in mind that most studies involving medications are funded by drug manufacturers, and this does not necessarily signify bias.

Future implications

• The combination of CCNU, TMZ, and radiotherapy may be indicated for patients with glioblastoma with methylated MGMT promoters; high-dose therapy may be considered in individuals who can tolerate it.
• Future clinical trials should be stratified according to a patient’s MGMT promoter methylation status.
• Additional, larger glioblastoma studies are warranted to establish this treatment regimen’s place in therapy.