COMBINED MODALITY TREATMENT OF NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME IN A REGIONAL NEUROSURGICAL CENTRE

Background

• Glioblastoma multiforme (GBM) is a common malignant brain tumor seen in adults; affected individuals tend to have poor outcomes, with a median survival of between 9 and 14.6 months.
• Recent research has demonstrated improved survival in patients who undergo neurosurgical resection and postoperative external beam radiotherapy with concomitant administration of temozolomide, followed by additional temozolomide therapy.
• Although maximal resection may improve survival, it is not always possible due to the infiltrative nature of the tumor, as well as its location.
• GBM prognosis is largely influenced by a patient’s age, performance status, and symptoms on presentation.

Objective

This study was conducted to determine the extent of surgery required to maximize survival outcomes in patients with GBM, when combined with adjuvant concomitant radiotherapy and temozolomide (Stupp protocol).

Title/Citation

Gauden AJ, Hunn A, Erasmus A, et al. Combined modality treatment of newly diagnosed glioblastoma multiforme in a regional neurosurgical centre. J Clin Neurosci. 2009;16:1174-1179. Epub 2009 Jun 18.

Funding

No financial support was received in conjunction with this publication.

Trial design

This was a retrospective, non-randomized, non-blinded evaluation conducted over 4 years (2004–2008) at a single center.

Enrollment

31 patients with a diagnosis of primary GBM were treated by the neurosurgical unit at the Royal Hobart Hospital, and were subsequently treated with a standardized radiotherapy/chemotherapy protocol.

Inclusion criteria

The study included patients with:

• Newly diagnosed and histologically confirmed GBM
• Good performance status
• Minimal neurological deficit

Exclusion criteria

Exclusion criteria were not provided.

Study groups

All patients underwent maximal possible tumor resection:

• Group 1: Complete macroscopic resection (9 patients; 29%)
• Group 2: Partial resection/debulking (15 patients; 48%)
• Group 3: Biopsy (7 patients; 22%)

This was followed by postoperative radiotherapy (median dose of 55.8 Gy applied in a median number of 31 fractions) with sensitizing temozolomide chemotherapy (75 mg/m² for 5 days/week), followed by a 6-month course of higher dose temozolomide (200 mg/m² for 5 consecutive days each month for 6 months).

End points

• Overall survival (OS)—survival time from the primary diagnosis
• Progression-free survival (PFS)—time from surgical treatment to tumor progression
• Adverse effects

Statistical analyses

• OS and PFS were compared for each surgical subgroup using the Kaplan-Meier method.
• The univariate Cox proportional regression model was used to assess the effect of prognostic factors on outcomes.
• Multivariate analyses were used to assess subgroups by age, gender, size and site of tumor, performance status, extent of resection, presence of symptoms, and use of steroids and anticonvulsants.

Baseline characteristics

• The median age at diagnosis was 62 years, with a range of 43 to 74 years.
• 39% of patients were female and 61% were male.
• 90% of patients had a Karnofsky performance score ≥70, indicating that they were able to work and carry on normal activities.
• All patients received corticosteroid therapy and 90% received antiseizure medication.

End points

OS:

• The median OS was 17 months; 9 patients (29%) were alive at the end of follow-up (38 months), and 2 (6%) had no evidence of residual disease.
• Complete or partial tumor resection improved OS compared with biopsy alone (19 months vs 9 months; P <.014).
• The extent of neurosurgical intervention significantly affected OS (P <.001). Median survival following complete macroscopic excision was 33 months, compared with 15 months following partial resection and 9 months following biopsy.
• Patients who presented with a seizure survived longer than those who did not (32 months vs 10 months; P <.025).
• There was a significant association between Karnofsky score and OS (P <.048).
• Tumor size and location did not influence OS.

PFS:

• The median PFS was 11 months.
• Complete or partial tumor resection improved PFS compared with biopsy alone (14 months vs 5 months; P <.045).
• The extent of neurosurgical intervention significantly affected PFS (P <.007). Median PFS following complete macroscopic excision was 28 months, compared with 7 months following partial resection and 5 months following biopsy.
• Patients who presented with a seizure had a longer median PFS than those who did not (28 months vs 7 months; P <.015).
• Performance status, tumor size, and location did not significantly influence PFS.

Adverse Effects:

• Radiotherapy was well-tolerated in all patients.
• Temozolomide was generally well-tolerated.
• 4 patients (13%) experienced temozolomide-related side effects; 2 (6%) had to discontinue therapy due to myelosuppression, 1 patient (3%) developed a petechial rash, and 1 patient (3%) experienced neutropenia.

Conclusions

• Patients with GBM who undergo radical tumor excision followed by adjuvant radiotherapy and temozolomide have an improved survival compared to patients who undergo subtotal excision or biopsy alone.
• Patients who present with acute symptoms (ie, seizure) have a better survival outcome than those with more chronic, subtle symptoms.
• Patients with better performance statuses have improved survival outcomes.

Study strengths/ limitations

Strengths:

• Investigators provided a strong rationale for conducting the study (ie, that recent research had demonstrated improved survival with the Stupp protocol, but the extent of surgery required to maximize outcomes remains unclear).
• All patients were treated by the same neurosurgical center using standard protocols, which helped to ensure consistency.
• The Kaplan-Meier method was appropriately used to assess survival outcomes over time.
• The lack of financial support from drug manufacturers reduced potential bias.

Limitations:

• The retrospective nature of this study made it difficult to control for confounding variables and to match demographics between groups.
• The study had a small sample size, which made it difficult to determine whether differences between groups were truly significant or simply coincidental.
• Research has revealed that a patient’s age and performance status influence GBM prognosis. However, investigators failed to indicate whether these factors were similar between study groups.
• The study excluded patients with a poor performance status, which may have diminished external validity.
• Investigators conducted several subgroup analyses, but failed to report all of the results.
• Investigators found that the extent of neurosurgical intervention affected survival, while tumor size and location did not; however, tumor size and location ultimately determined the extent of surgery that could be done, thus these factors may indeed have been influential.

Future implications

• The Stupp protocol, with maximal surgical resection, should be considered in eligible patients with GBM; it may be particularly beneficial in patients with a good performance status, as well as those who present with acute symptoms.
• Larger, prospective, randomized, clinical trials must be conducted to compare different levels of surgical resection against survival rates, to confirm the findings of this study.
• Further research should be conducted to determine the impact of seizure history on GBM prognosis and treatment.