GBM

Glioblastoma Multiforme

  • 75% of all high-grade gliomas
  • Histopathologic features of GBM
    • Nuclear atypia
    • Mitotic activity
    • Vascular proliferation
    • Necrosis
  • Any three of these suffice to make the diagnosis

MRI

  • Vasogenic edema
  • Ring enhancement
  • Central necrotic regions

Median Survival—> 1yr.

Predictors for survival :

  • Patient factors
    • Age at diagnosis
      • <50 do better than >50
    • Karnofsky performance status
  • Disease factors
    • Tumor histology
    • Duration of neurologic symptoms
    • Frontal lobe —> improved survival compared to those with parietal or temporal lobe lesions
  • Treatment factors
    • Extent of surgical resection
    • Radiographic response

Recursive Partitioning Analysis (RPA)
Classification of patients into groups with similar outcomes, analyzed data from three RTOG trials

Class Patient Characteristic Survival
I,II Anaplastic Astrocytoma <50yr&Normal Mental St. OR >50yr&KPS>70&symptoms>3m 40-60m
III,IV Anaplastic Astrocytoma <50yr&AbNl Mental St. OR >50yr&symptoms<3m 11-18
GBM <50yr OR >50y&KPS>70 11-18
V,VI GBM Age >50 y, KPS <70 or abnormal mental status 5-9

Treatment

Historically—> Sx+RT
Now new standard of care —> Sx+RT+Concurrent Temodal

Adjuvant Radiation

  • We know adding radiation increase survival from 5m to 10m.
  • RT is effective in elderly as well.
    • WBRT 46-60Gy has been used
      • Now 60Gy/30 is standard treatment.
        • In Toronto in elderly >70 40Gy/15 is prescribed without Temodal.
          • This is based on Roa Study.
          • Temodal is saved for recurrence.

RTOG description:

  • First 46 Gy/23
    • Volume should include the GTV+edema on pre-op CT/MRI scan+2cm
      • If no edema==>margin should be 2.5 cm.
  • Boost 14 Gy/7
    • GTV (without edema) on the pre-op MRI/CT scan + 2.5cm

Radiotherapy Target Volume

Even though GBM is a disseminated disease, localized RT is the standard of care.

  • There are comparable outcomes to WBRT
  • We know that 80-90% recurrence is local (within 2cm of enhancing tumor on CT) <— according to autopsy reports.
  • The benefit is avoidance of neurotoxicity associated with WBRT
  • If multifocal —>WBRT may be recommended
  • We know with covering edema and wider margin there is a better chance to cover histologic tumor.

Radiotherapy Dose

  • Standard therapy:60Gy/30
    • Significant improvement in median survival from 28-42 weeks in the groups treated with doses > 50-60Gy
      • 60Gy:12m
      • 45Gy:9m

Shorter course of treatment if:

  • Poor performance status
  • Elderly
  • Roa STUDY
    • 100 patients
    • > 60yrs
    • Arms:
      • 60 Gy / 30
      • 40 Gy / 15
    • OS the same!

Dose Escalation and Altered Fractionation

A benefit for doses >60 Gy using conventional treatment has not been demonstrated
Several accelerated hyperfractionation regimens to doses over 70 Gy have been investigated, also without significant improvement in survival.

  • RTOG-ECOG
    • 253 patients
    • Arms
      • 60 Gy given in 6 to 7 weeks
      • 60 Gy plus a 10-Gy boost to a limited volume given in 7 to 8 weeks
    • No benefit for the higher irradiation dose.

Shin study

  • Randomized
  • showed the benefit of 61.4 Gy in 69 fractions of 0.89 Gy given three times daily over 4.5 weeks or conventional fractionation to 58 Gy in 30 fractions given once daily over 6 weeks
  • Median survival : 39 and 27 weeks & 1-year survival rates were 41% and 20%, respectively (p < .001).
  • Other studies failed to show benefit for accelerated and hypo-fractionated regimen.

RTOG 8302

  • Prospective, randomized phase I/II trial
  • Malignant Glioma
  • 747 Patients
  • Dose Escalation
    • Twice daily fractionation
    • 64.8 Gy
    • 72.0 Gy
    • 76.8 Gy
    • 81.6 Gy
    • ALL Given in 1.2 Gy fractions twice daily
  • Accelerated Hyperfractionated regimens
    • Twice daily fractionation
    • 48 Gy
    • 54.4 Gy
    • 1.6 Gy twice daily
  • Patients also received chemotherapy with BCNU

An early report from this trial:

  • 72-Gy arm at the cost of increased toxicity with higher doses & quality-adjusted survival: significantly improved in the 72 Gy group Final report:
  • No significant differences between the treatment arms
  • Late toxicities were slightly increased with higher doses

RTOG phase III trial

  • Arms:
    • 60 Gy in 30 daily fractions
    • Hyper-fractionated RT: 72 Gy in 60 fractions of 1.2 Gy given twice daily
  • No difference in survival was found

Dose Escalation Using Radiosurgery and FSRT

No evidence to increase survival.

  • Only one retrospective study suggested benefit.
  • Not shown in prospective studies.

RTOG 0023

  • Seventy-six patients with GBM
    • with postoperative residual tumor plus tumor cavity diameter <60 mm
  • Treated with 50 Gy standard radiotherapy in daily 2 Gy fractions, plus four FSRT treatments given once weekly during weeks 3 to 6 of radiotherapy. The FSRT dose was either 5 Gy or 7 Gy per fraction for a cumulative dose of 70 or 78 Gy in 29 treatments over 6 weeks.
  • Significant toxicity included three patients with acute grade 4 toxicity (neurologic, constitutional, metabolic) and one with grade 3 late necrosis.
  • The median survival time was 12.5 months.
  • Overall, no survival advantage
  • Subset analysis
    • Those who had undergone gross total resection
      • Median survival time of 16.6 compared with 12.0 months for historic controls (p = .14)
        • Suggesting that patients with minimal disease burden may benefit from this form of treatment

Dose Escalation Using Brachytherapy

Laperriere used brachytherapy as a boost to conventional radiotherapy

  • No benefit in survival

survival was 12.7 months. Prospective, randomized trials are needed for further evaluation.

Radiosensitizers

Studies using radiation modifiers in conjunction with radiotherapy to overcome the hypoxia present in malignant gliomas have generally shown disappointing results.

Chemotherapy

Currently the standard of care.

Adjuvant treatment with nitrosoureas has been justified by trials showing a small long-term survival benefit:

  • 1-year survival rate of 6%, from 40% to 46%, and a 2-month increase in median survival time

NCIC, EORTC

  • Stupp et al
  • Phase III
  • Arms
    • 60 Gy/30
    • 60 Gy/30 + concomitant daily temozolomide (75 mg/m2/day) followed by up to six cycles of maintenance temozolomide (150 to 200 mg/m2/day on days 1 to 5 every 28 days)
  • Improved median survival
    • 26%
  • Improved 2 year Survival

*10%

  • Toxicity
    • 7% grade 3 & 4 hematologic toxicity
    • None in the group treated with radiotherapy alone.
  • Significant survival benefit in patients with GBM treated with concomitant and adjuvant temozolomide

TEMODAL

  • Oral alkylating agent ( or METHYLATING agent )
  • The active metabolite MTIC adds methyl residues to nucleotides in the DNA molecule.
    • Methylation of the O6 position of guanine is the key to its cytotoxic effect. => will form O6-methylguanine
  • Cross the BBB

Damage by temodal is defended by three repair mechanisms:

  • 06-alkylguanine-DNA alkyltransferase (ATase) ( MGMT )
    • Repair of methylated DNA adducts is mediated by the DNA repair enzyme MGMT which removes alkyl(methyl) adducts from DNA in a single step mechanism without co-factors. (which counteracts the action of TEMODAL )
  • DNA mismatch repair.
  • Poly (ADP-ribose) polymerase.

MGMT

  • O6-methylguanine-DNA methyltransferase (MGMT)
  • Enzyme responsible for DNA repair
  • Removes methyl groups from the O6 position of Guanine and MGMT become methylated itself
    • ==> Allow cell to avoid apoptosis
    • MGMT become consumed and must be regenerated for further activity
  • Possible explanation for differing responses to chemoradiotherapy
  • The gene that encodes for MGMT is located on chromosome 10q26
  • Loss of function of this gene is most often due to epigenetic changes
    • Promoter-region methylation
      • => lack of MGMT expression
    • Silencing of the MGMT gene through methylation => increased overall survival and better response to treatment with temozolomide and BCNU in patients with gliomas

Important study of Hegi

  • Evaluated the methylation status of the MGMT gene promoter region (through PCR)
  • MGMT promoter methylation:in 45% of assessable patients
  • Median overall survival, irrespective of treatment assignment, was increased in patients with methylated MGMT
    • 18.2 months vs 12.2 months(non-methylated) p < .001
  • With treatment assignment
    • OS benefit with temozolomide to radiotherapy was seen only in patients with MGMT promoter methylation
    • Methylated MGMT: median overall survival was 21.7m(RT+Temodal) vs 15.3m(RT alone)(p = .007)
    • Non-methylated MGMT: non-significant difference in the median overall survival
      • 12.7 months vs 11.8 months

Targeted Therapies
EGFR gene amplification is seen in approximately 40% to 50% of patients with GBM. EGFR is associated with control of cell growth through autocrine and peregrine effects of growth factors. Inhibitors of EGFR tyrosine kinase such as gefitinib and erlotinib and EGFR antibodies have shown activity against GBM in early clinical trials (198,257). However, in a study by Chakravarti et al. (36), EGFR levels as measured by quantitative immunohistochemistry were not of prognostic value for patients with newly diagnosed GBM. Response to gefitinib did not correlate with tumor EGFR status in a study by Uhm et al. (251). The presence of an EGFR deletion mutant variant III, leading to a constitutively active variant of a key cell survival pathway, and the presence of intact PTEN, a downstream inhibitor of this signaling pathway, have been found to be significantly associated to clinical response to EGFR kinase inhibitors in patients with GBM (145). Further studies are needed to define the significance of EGFR mutations and downstream regulators of associated pathways.
Mutations and loss of the PTEN gene are encountered in approximately 70% of patients with GBM. PTEN inhibits signaling through the PI3-kinase and AKT signaling pathway. Loss of PTEN results in loss of effectiveness of EGFR inhibitors, probably due to constitutive signaling through PI3-kinase, which bypasses any upstream EGFR inhibitor effect. Specific inhibitors such as CCI-779, RAD 001, and rapamycin are in clinical testing. Preclinical experiments suggest that these agents are potential radiosensitizers (193).
Neovascularization is a major feature of GBM, and many studies demonstrate that GBM secrete VEGF in abundance. The
P.735

supporting endothelium strongly express receptors for VEGF. Strategies inhibiting angiogenesis are under active investigation and include agents such as bevacizumab, an antibody to VEGF. In a recent report of 10 patients with recurrent GBM, four achieved an objective response within a few days (as early as 18 days) of administering bevacizumab (185). In particular, the โ€œfluffyโ€ enhancing areas responded best, but nodular tumors responded less well. There was striking reduction in peritumoral edema, implying that bevacizumab has considerable effect on restoring the BBB, which could prove to have therapeutic value. Initial trials with other agents such as enzastaurin, which inhibits VEGF signaling by inhibiting protein kinase cฮฒ2, have been tested with encouraging response rates (69), but follow-up trials failed to yield the expected results and further development of this agent was terminated; nevertheless, interest in inhibitors of angiogenesis remains high, especially with early promising results using bevacizumab which is currently being actively investigated.
Treatment at Recurrence
Although several therapeutic options have been considered for patients with recurrent GBM, none are curative and therefore the management goals should be palliative. Hospice referral for palliative care is reasonable for many patients. Medical management consists of appropriate use of steroids and anticonvulsants. Palliative debulking may help selected patients by relieving mass effect, but survival following a second resection is usually very short. The use of polymer-based local chemotherapy (carmustine wafers) has been tested in a randomized trial that included 222 patients with recurrent glioma (mostly GBM); survival increased from 44% to 64% at 6 months (p = .02) for patients with GBM, and median survival from 23 to 31 weeks (23). Systemic chemotherapeutic agents have been tested mostly in the context of clinical trials and have been uniformly disappointing (102), as have targeted agents with the notable exception of EGFR tyrosine kinase inhibitors in patients with recurrent GBM expressing wild type PTEN and mutant EGFR (145). Of 37 patients with recurrent GBM treated with EGFR tyrosine kinase inhibitors at UCLA there were seven responders, while 19 had early progression. Coexpression of mutant EGFR and wild type PTEN had 86% sensitivity, 89% specificity, and a positive predictive value of 75% for response.
Repeat radiotherapy using one of several different methods (including radiosurgery, brachytherapy, GliaSite balloon brachytherapy, and even repeat external beam radiotherapy) may be considered for carefully selected patients (203).
Evidence-Based Treatment Summary
Maximal surgical resection, although not tested in a prospective trial, is generally associated with more favorable outcome and is recommended whenever feasible.
Postoperative radiotherapy has been shown to provide a survival advantage in several clinical trials. The typical radiotherapy dose is 60 Gy in 6 weeks; dose escalation strategies have generally failed. Although there is much interest in incorporating advanced imaging in treatment planning and in using newer treatment modalities, their benefits in GBM remain to be demonstrated.
Temozolomide, given during and after radiotherapy, provides a significant survival advantage that is greatest in patients with methylation of the promoter region of the MGMT gene.