Low Grade Glioma
  • Slow-growing tumors
  • 10% of all primary intracranial tumors in adults
    • 20% of patients with gliomas

Two major Subtypes:

  • Prognostic Factors for low grade gliomas:
    • Age
      • >40yr —> worse prognosis
    • Histology
      • Astrocytome do worse than oligodendroglioma
    • Size of tumour
      • If >6cm —> worse
    • Presence of tumour across midline
    • Extent of Resection
    • Mental Status

Pilocytic Astrocytoma

Pilocytic astrocytoma = Juvenile Pilocytic Astrocytoma=WHO grade I treatment

Rosenthal_HE_40x.jpg
  • Glioma matrix with intemixed Rosenthal fibers.
  • More common in children
  • Well circumscribed enhancing lesions
    • Often with a cystic component

Treatment

  • More amenable to total resection than other low-grade gliomas
  • Fenestration of the cyst and resection of the mural nodule
    • Usually curative
    • In tumors in which the wall of the cyst enhances, cystic degeneration of a larger tumor is more likely, and resection of the entire cyst is necessary.

Complete resection

  • associated with excellent survival
  • >90% : cured
  • No adjuvant therapy is necessary

Incomplete resection

  • Long-term survival(10yr): 70% - 80%
  • Role of adjuvant treatment unclear:
  • Chemo has no established role.
  • Benefit of postoperative radiotherapy is unclear
    • Usual recommendation is for close follow-up
    • Some evidence of improved progression-free survival
    • Factors to consider:
      • Location of the tumor
      • Extent of residual disease
      • Feasibility of repeated surgical excision
      • Availability for F/U
      • 50 to 55 Gy (1.8 to 2 Gy fractions)

Nonpilocytic/Diffusely Infiltrating Gliomas

Nonpilocytic Glioma=diffusely infiltrating low-grade gliomas=WHO grade II tumors

  • May arise from:
    • Astrocytic
    • Oligodendrocytic
      • usually Calcification is seen in CT
    • Mixed lineage
  • 3rd - 4th decade of life
  • Ill-defined, diffuse, nonenhancing low-density region
  • Location in brain:
    • Frontal
    • Temporal lobes
  • MRI : more sensitive
    • Hypointense and nonenhancing on T1-weighted images and hyperintense on T2-weighted images

Pathology:

  • Well differentiated
  • Lack mitoses, nuclear pleomorphism, anaplasia, vascular proliferation, and necrosis
  • Differentiation from reactive gliosis can be difficult
  • Histologic subtypes:
    • Low-grade astrocytomas
    • Fibrillary
    • Protoplasmic
    • Gemistocytic
      • Behave in a fashion more consistent with a malignant glioma.

Good Prognostic Factors

  1. Young age
  2. Good neurologic status
  3. Oligodendroglial subtype
  4. Low proliferation indices
  5. Size <6cm

Unfavorbale Prognostic Factors

  1. Ki-67 (MIB-I) index >3%
  2. Malignant transformation
  3. Age 40 or older
  4. Astrocytoma histology
  5. Maximum diameter >=6 cm
  6. Tumor crossing the midline
  7. Presence of neurologic deficits

Low Risk:

  • <=2 factors (3 to #7)
  • Median Survival : 7.7 years

High Risk:

  • >3 Factors
  • Median Survival : 3.2 years

Overall Prognosis:

  • Median survival :
    • 5 years for patients with astrocytoma
    • 10 years for patients with oligodendroglioma
  • 5-year survival rate
    • 37% for patients with astrocytoma
    • 56% for mixed oligoastrocytoma
    • 70% for oligodendroglioma

Molecular Diagnosis:

  • Loss of 1p & 19q
    • 44% of oligodendrogliomas
      • Of which 65% were low grade
      • Combined loss of 1p & 19q —> associated with an improved probability of survival, independent of other factors such as age
  • Median Survival if combined loss of 1p amd 19q : 14.9 years
  • Median Survival without 1p and 19q deletions : 4.7 years
  • Also 1p deletion correlated with better response to chemotherapy

There are two large European phase III trials for low-grade glioma

  • To examine the dose and timing of postop RT
    • EORTC 22844
    • EORTC 22845

Treatment

  • Timing and incication fo adjuvant treatment is controversial.
  • In general, early intervention is indicated for:
    • Increasing symptoms
    • Radiographic progression
    • High-risk features suggestive of transformation to a higher-grade tumor

Observation and Serial Imaging is an option for :

  • In younger patients (<40 years)
  • Complete resection

Post-Op RT:

  • Subtotal resection
  • High-risk features
  • 50 Gy in 1.8 Gy fractions
  • Chemotherapy may have a role
    • Specially in those with loss of 1p and 19q

Surgery

Goal of surgery and its timing are still debated.

  • Mostly to establish the diagnosis and to determine histology, grade, and molecular characteristics that affect treatment.
  • Uder the best circumstances, total resection with an adequate margin is rarely achieved due to the diffusely infiltrative nature of these tumors and involvement of eloquent regions
    • Most studies have found total or subtotal (>90%) resection to be associated with improved outcome
  • Surgical resection is unlikely to be curative

RTOG 98-02

Good risk Patients:

  • Age <40
  • Gross total tumor resection
  • Median time to progression —> 5 years

Radiotherapy

Low-grade glioma scoring systems

Criterion Points (yes/no) ( Each yes would get 1 point )

2008 LGG scoring system (UCSF)

  • Age >50
  • KPS ≤80
  • Eloquent location (presumed)
  • Maximum diameter >4 cm

low = 0–1 points, medium = 2 points, high = 3–4 points

2002 LGG scoring system (Pignatti et al.)

  • Age ≥40 y
  • Astrocytoma histology
  • Maximum diameter ≥6 cm
  • Tumor crossing midline
  • Neurologic deficit

##purple:low = 0–2 points, high = 3–5 points##

Low Risk:

  • Observed postoperatively
  • RT at disease progression or recurrence

Where did that we get from:

This practice is based on the results of a phase III trial by Van den Bent et al. in EORTC 22845

EORTC 22845
  • Prospective Randomized Trial
  • 314 : Low-grade gliomas
  • Arms:
    • Postoperative radiotherapy to 54 Gy in fractions of 1.8 Gy (n = 157)
    • RT at progression (n = 157)
  • A significant improvement in median progression-free survival was found with early radiotherapy
    • 5.3 vs 3.4 years (p <.0001)
    • NO difference in median survival, 7.4 versus 7.2 years (p = .872)
  • 65% the patients in the delayed radiotherapy group received radiotherapy at progression.
  • Malignant transformation occurred in 65% to 72%
    • No difference between the two groups
  • Better seizure control was superior in the early RT

Conclusion: Post-Op RT appropriate in some situations, for example, patients with symptomatic lesions, withholding radiotherapy until tumor progression does not jeopardize survival.

EORTC 22844
  • Randomized Prospective Trial
  • 379 patients
  • All post-op Rt but different dose/fractionation
  • Arms:
    • 45 Gy in 5 weeks (1.8Gy/fr)
    • 59.4 Gy in 6.6 (1.8Gy/fr)
  • Overall Survival SIMILAR
    • 58% vs. 59%
  • Progression-Free Survival SIMILAR
    • 47% vs. 50%
North Central Cancer Treatment Group (NCCTG), RTOG, and ECOG study
  • Randomized
  • 203 patients
  • Arms:
    • Low-dose RT : 50.4 Gy/28fr (1.8Gy/fr)
      • 2yr and 5yr Survival : 94% and 72%
      • Grade 3-5 Neurotoxicity: 2.5%
    • High-dose RT : 64.8 Gy/36fr(1.8Gy/fr)
      • 2yr and 5yr Survival : 85% and 64%
      • Grade 3-5 Neurotoxicity: 5%
  • No significant difference in Progression-Free Survival or Overall Survival

Consequently low-dose radiotherapy, 50 Gy in 1.8 Gy fractions, is the standard of care for patients with low-grade gliomas. The target volume is local, with a margin of 2 cm beyond changes demonstrated on traditional MRI sequences. Using FLAIR images, which usually show abnormality beyond any enhancing or nonenhancing tumor, a smaller margin of 0.8 to 1 cm may be used.

lowgradegliomart.bmp
Chemotherapy

No established role for chemotherapy in adult patients with low-grade gliomas.

Southwest Oncology Group (SWOG)
  • Randomized
  • 60 patients
    • Incompletely excised low-grade gliomas
  • Arms:
    • RT alone (55 Gy in 6.5 to 7 weeks)
    • RT + CCNU
  • Median Survival
    • 4.5 years for RT alone and 7.4 years for RT + CCNU (p = .7)
  • This trial was closed early due to slow accrual. It has been argued that continued enrollment may have led to a significant difference in survival considering the large difference between the two arms.
RTOG 98-02
  • Multiagent chemotherapy, in particular PCV, appeared promising with response rates ranging from 50% to 80% in recurrent and newly diagnosed tumors
  • 251 unfavorable patients
    • Age 40 or greater
    • Subtotal resection or biopsy
  • Arms:
    • RT alone to 54 Gy in 30 fractions
      • Overall Survival at 2yr: 87%
      • Overall Survival at 5yr: 61%
      • Acute grade 3 or 4 toxicity : 67%
    • RT + 6 cycles of standard dose PCV
      • Overall Survival at 2yr: 86%
      • Overall Survival at 5yr: 70%
      • Acute grade 3 or 4 toxicity: 9%
  • Progression-Free Survival was not different
  • Temozolomide has been shown to have activity in phase II trials in newly diagnosed and recurrent low-grade gliomas.
EORTC 22041
  • A phase III trial
  • Arms:
    • RT 50.4 Gy and temozolomide with stratification of 1p and 19q allele status.

Evidence-Based Treatment Summary

  1. Maximal surgical resection, although not tested in a prospective trial, is generally associated with more favorable outcome and is recommended whenever feasible.
  2. Postoperative radiotherapy has not been shown to provide a survival advantage in the only clinical trial testing this question, although progression-free survival and seizure control were superior.
    • The typical radiotherapy dose is 45 to 54 Gy; randomized trials do not show a survival advantage with higher doses.
  3. CCNU and PCV do not provide a survival advantage over radiotherapy alone.
  4. Temozolomide has not been tested in a phase III trial.