You decide to biopsy the small lesion in the right temporal lobe. The pathologist tells you that he or she sees some astrocytosis and possibly a low-grade glioma, but he or she is unable to confirm the diagnosis.

During your initial management, the patient responds at first to fluids, resuscitation, and electrolyte corrections and gets better. However, she starts to deteriorate over the next few hours; she becomes more lethargic and harder to arouse.

• The MRI shows again the two lesions described above in the CT findings.
  
• Of note is that the large mass appears to have a “popcorn-like” appearance with old and new hemorrhage within the lesion as well as a hypointense rim on fluid-attenuated inversion-recovery (FLAIR) sequences.

• Present all options to the patient, including1–3
  
  
  
  • Observation/no treatment
    
  • Stereotactic biopsy of the left frontal lesion
    
  • Open biopsy or resection of the left frontal lesion
    
  • Stereotaxic biopsy of the nondominant right-sided lesion appears to be the least risky procedure and is the authors’ preferred choice.
  
  
• Consider obtaining an angiogram.
  
• Also consider obtaining MR spectroscopy, cultures (blood, urine).

• Differential diagnosis of further deterioration
  
  
  
  • Hemorrhage into the mass
    
  • Diffuse worsening of edema
    
  • Trapped ventricle with hydrocephalus
    
  • Deteriorating hypothalamic function

• Given that the diagnosis remains unclear, the patient needs further treatment and investigations for causes of deterioration. Consider
  
  
  
  • Urgent CT of the head
    
  • Continuing steroids
    
  • Repeating electrolytes, coagulation profile, and other laboratories
  
  
• In this case, the deterioration was due to a trapped ventricle from increasing edema and the patient was treated with a ventriculostomy. She did improve postprocedure and remained more awake for about a week, at which point a stereotactic biopsy of the larger lesion was considered.
  
• This final diagnosis was of GBM. The sequence of steps outlined above in her management is important, however, even though the final outcome is still dismal in retrospect.

• According to the Stupp protocol⁴: Temozolomide (Temodal; Schering-Plough, Kenilworth, NJ) – a methylating agent is administered concomitantly and sequentially with radiotherapy (RT) as follows:
  
  
  
  • RT: 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy
    
  • Concomitantly administer daily temozolomide 75 mg/m², 7 days a week from the first to the last day of RT
    
  • Sequentially, beginning 4 weeks after the end of concomitant administration:
    
    
    
    • Six cycles of temozolomide 150 to 200 mg/m² once daily on days 1 to 5 of a 28-day cycle

• In this case, due to the poor Karnofsky performance score and the underlying metabolic disorder, the survival will be less than the expected median survival generally quoted for GBM^5,6 :
  
  
  
  • Concomitant RT + temozolomide:
    
    
    
    • Median survival: 14.6 months
      
    • Two-year survival rate: 26.5%
    
    
  • RT alone:
    
  • Median survival: 12.1 months
    
    
    
    • Two-year survival rate: 10.4%

• Glioma progression pathway⁶ (Fig. 15.2)
  
  
  
  • Precursor cells may progress to
    
    
    
    • Diffuse (grade II) astrocytoma
      
    • Then to anaplastic (grade III) astrocytoma
      
    • Then to secondary GBM (grade IV)
      
    • They are associated with TP53 mutation in 60% of cases, which present as primary (de novo GBM).
    
    
  • GBM is associated with epidermal growth factor receptor amplification or overexpression.
    
  • Oligodendroglioma development is associated with chromosome 1p and 19q loss of heterozygosity.

• Epigenetic mechanisms of action of temozolomide on malignant glial tumor DNA and opposing MGMT (O⁶-methylguanine–DNA methyltransferase) repair is summarized below (Fig. 15.3)^4,7,8 :
  
  
  
  • Temozolomide (Temodal) is an alkylating agent that adds a methyl group to guanine (one of the four DNA bases). The product is O⁶-methylguanine DNA.
    
  • This initiates a futile recycling of the mismatch repair pathway causing DNA strand breaks and apoptotic tumor cell death.
    
  • MGMT is a DNA repair enzyme that repairs the damaged tumor DNA through a stoichiometric reaction by removing the methyl group.
    
  • If the MGMT promoter gene is methylated, then MGMT is inactive and the tumor cells are not protected from temozolomide.
    
  • MGMT is a suicide enzyme because it protects tumor cells from temozolomide.