Glioblastoma (GBM) in elderly patients: A randomized phase III trial comparing survival in patients treated with 6-week radiotherapy (RT) versus hypofractionated RT over 2 weeks versus temozolomide single-agent chemotherapy (TMZ)

Reporter: Samuel Swisher-McClure, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 5, 2010

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Presentor: A. Malmstrom
Affiliation: Unit of Advanced Palliative Home Care, Linköping, Sweden

Background

  • Glioblastoma Multiforme (GBM) is the most common primary malignant brain tumor, accounting for 40% of primary CNS Malignancies
  • The incidence of GBM increases with age and approximately 50% of patients diagnosed with GBM are > 65 years old.
  • Standard therapy includes maximally safe surgical resection, targeted radiotherapy (RT), and chemotherapy.
  • Known prognostic factors include age, performance status, extent of resection, and neurologic function at the time of presentation.
  • Despite aggressive therapy, elderly patients with GBM have a particularly poor prognosis with observed survival typically < 12 months.
  • Optimal therapy of GBM in the elderly remains an area of controversy
    • A study conducted in France by Keime-Guibert et al. (NEJM, 2007) randomized 85 patients with GBM aged ? 70 years to either radiotherapy (50 Gy given in 6 weeks) or supportive care alone. This trial was closed early after an interim analysis showed a significant overall survival improvement in the radiotherapy group (Median Survival 29.1 weeks vs. 16.9 weeks respectively).
    • A randomized trial published by Roa et al. (JCO, 2004) randomized 100 patients with GBM aged ? 60 years to receive either hypofractionated radiotherapy (40 Gy given over 3 weeks) or standard high dose radiotherapy (60 Gy given over 6 weeks). The authors observed no significant difference in overall survival between the two study groups.
    • A phase III randomized study published by Stupp et al. (NEJM, 2005) demonstrated an overall survival benefit associated with the addition of concurrent and adjuvant Temozolomide (TMZ) compared to standard high-dose (60 Gy) radiotherapy alone ( 2 yr Overall Survival 27.2% vs. 10.9%). However, this study was limited to patients aged ? 70 years. 
    • Brandes et al. (Cancer, 2009) have published data from a single-arm study of patients with GBM aged ? 65 years treated with high-dose radiotherapy (60 Gy in 6 weeks) with concomitant TMZ. The authors of this study reported a median overall survival of 13.7 months.
    • A Phase II Study published by Chinot et al. (Cancer, 2004) examined patients with GBM aged ? 70 years treated with TMZ alone as first line therapy and reported a median overall survival of 6.4 months. These results are comparable to previously published results of treatment for elderly GBM patients with radiotherapy alone.
  • Based upon this data, the authors proposed treatment of elderly GBM patients with TMZ alone as an alternative to RT.

Methods

  • The study was a multi-institutional, phase III randomized trial comparing two different RT schedules with single-agent TMZ chemotherapy in older patients with GBM.
  • Inclusion Criteria:
    • Patients with newly diagnosed GBM age ? 60 years
    • WHO PS 0-2
    • No prior chemotherapy or radiation for GBM
    • All patients were required to have an anticipated life expectancy of at least 3 months
  • Randomization treatment groups:
    • High dose, conventionally fractionated RT (60 Gy in 2 Gy fractions over 6 weeks)
    • Hypofractionated RT (34 Gy in 3.4 Gy fractions over 2 weeks)
    • 6 cycles of chemotherapy with TMZ (200 mg/m2 days 1-5 every 28 days)
  • Follow-up included quality of life surveys and symptom checklist. These, as well as steroid dosing, were assessed at 6 weeks, 3 months, and 6 months after start of treatment.
  • The primary study end point was overall survival (OS).
  • The authors used an intention to treat analysis.

Results

  • A total of 342 pts were enrolled.
    • 291 pts were randomized between all 3 of the treatment options
    • 51 pts were randomized between either hypofractionated RT and TMZ because of individual preference of the treatment center
  • The authors reported that the three treatment arms were well balanced with regard to clinical prognostic and demographic factors.
    • The median patient age was 70 years (Range 60-88)
    • The majority of patients were reported as having good performance status (WHO PS was 0-1 for 75% of pts).
    • There was a slight male predominance in the enrolled study patients (59% male and 41% female).
    • 72% of patients had undergone tumor resection (Either Gross total or Subtotal Resection), while the remaining 28% had a diagnostic biopsy only.
  • Within the high dose RT treatment group, 31% of patients failed to complete all prescribed treatment as planned, primarily due to a reported deterioration of clinical condition.
  • In the TMZ alone group, 40/119 patients (33.6%) received salvage radiotherapy during the study period for tumor progression.
  • Survival data are available for 334 pts (98%), with 11 pts (3%) alive.
  • The authors reported a statistically significant difference in OS when comparing TMZ alone to high dose RT, with median overall survival times of 8.3 months for TMZ alone, and 6.0 months with high-dose RT.
  • There was no significant difference in overall survival observed between the patient groups receiving hypofractionated RT vs. TMZ alone.
  • Subgroup analyses of patients aged 60-70 years and those aged > 70 years were also performed
    • In patients aged 60-70 years, there were no observed significant differences in overall survival between the 3 treatment arms.
    • In patients aged >70 years, there were significant differences in overall survival between the 3 treatment groups, with reported median overall survival times of 9.0 months with TMZ alone, 7.1 months with hypofractionated RT, and 5.2 months with High-dose RT.
  • The authors did not report details of adverse events for the treatment groups, quality of life data, or biomarker data such as MGMT mutation status.

Author's Conclusions

  • GBM in the elderly is a disease associated with a very poor prognosis and is almost universally fatal. The authors note that efforts should be made to avoid time-consuming and potentially toxic therapy without improvement in overall survival.
  • There was no significant advantage to High-Dose RT compared to Hypofractionated RT, or 6 cycles of TMZ chemotherapy.
  • These results suggest that high-dose RT may be safely avoided and perhaps should not be offered to elderly patients with GBM.
  • Chemotherapy with TMZ alone appears to be a safe alternative to RT.
  • Additional subgroup analyses and determination of molecular markers is ongoing.

Clinical Implications

  • GBM is the most common primary CNS malignancy in adults, and is associated with a particularly poor prognosis when diagnosed in elderly patients.
  • Previous studies have shown an overall survival benefit associated with radiotherapy in elderly patients with GBM compared to supportive care alone.
  • Elderly patients can be a very heterogeneous group with wide variance in performance status and underlying medical problems, making this a challenging group of patients to study.
  • Temozolomide is a well-tolerated oral chemotherapeutic agent that has demonstrable benefit in patients with GBM. However, the trial published by Stupp et al. showing an overall survival benefit with concurrent TMZ + RT vs. RT alone did not include patients over the age of 70.
  • Previously published non-randomized data suggests that either TMZ or RT alone result in similar overall survival rates in elderly patients with GBM.
  • The current study is a randomized controlled trial which compared two different fractionation schedules of radiotherapy with TMZ alone in patients diagnosed with GBM aged ? 60 years.
  • The authors reported a significant improvement in overall survival for patients treated with TMZ alone when compared to patients receiving high-dose RT.
  • However, the study has several limitations which include:
    • The study compared TMZ alone to radiotherapy alone for GBM when the best results in the elderly patient group have been observed when TMZ and RT are combined (Brandes et al. Cancer, 2009).
    • The NCCN guidelines currently include a category 2B recommendation for combined RT and TMZ in patients with GBM aged > 70. This indicates that this is an area of controversy, but a randomized trial to determine best practice should include combined modality therapy for these patients.
    • The median overall survival times observed in the study are markedly inferior to previously published data from studies of combined chemoradiation.
    • In the current study, a relatively large number of patients in the high-dose RT treatment group (31%) failed to complete the prescribed course of therapy and further details regarding adverse events among these patients were not presented.
    • Approximately 1/3rd (33.6%) of patients assigned to the TMZ treatment arm received salvage radiotherapy during the study period for tumor progression which could contaminate the results of this treatment group.
    • The authors did not present quality of life data among the three treatment groups which would be an important consideration given the poor prognosis of this disease.
    • Information regarding patient biomarkers such MGMT mutation status are not yet available. This information could potentially be used to identify patient groups who are most likely to benefit from treatment.
  • While the current study provides evidence that Temozolomide alone provides comparable benefit compared to radiotherapy alone in elderly patients with GBM, further studies are needed to determine whether these patients may benefit from combined TMZ + RT which is the current standard of care in patients < 70 years of age.


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