Glioblastoms Multiforme (GBM) -Pathology -Clinical features -Investigation -Management -Radiotherapy Planning

2. Out line of presentation
• Introduction (Anatomy , Pathology, CF,
Investigations, Prognosis & management options)
• Patient positioning & simulation
• RT dose & fractionation
• OAR
• Toxicity
• GBM in elderly

3. Introduction
I) Anatomy
• CNS is enveloped by three meningeal layers.
• The pia & arachnoid layers referred to as the
leptomeninges, & within them is the
subarachnoid space, which is filled with CSF.

4. Introduction…
II) Pathology
• Primary brain tumors are uncommon & comprise
only 3 % of all cancers
• Metastatic spread to the brain from primary
cancers elsewhere in the body is much more
common

5. Introduction…
• II) Pathology-Glioma
• Account for half of all primary brain tumors in adults.
• They arise from glial cells and are classified by cell
type into :
Astrocytomas
Ependymoma
Oligodendroglioma
• They present in any age group, although most occur
in late adulthood
• Malignant glioma includes anaplastic glioma (WHO
grade III) and GBM (WHO grade IV).

6. Introduction…
• II) Pathology-GBM
• GBM accounts for approximately 75% of all high-
grade gliomas.
• The histopathology features of GBM include:
Nuclear atypia
Mitotic activity
Vascular proliferation
Necrosis; any three of these suffice to make the
diagnosis.

8. Introduction…
III) Clinical Features
• No specific symptom constellation is
pathognomonic of HGG
• May present with symptoms of ↑ ICP , including
headache, nausea and vomiting, cognitive or
behavioral problems, focal neurological deficits or
seizure.

9. Introduction…
IV) Investigation
• They are best evaluated with MRI but the infiltrative
nature of HGG makes it difficult to determine tumour
margins accurately
• More sophisticated, biologically based imaging
platforms are critically needed to evaluate :
the true extent of disease at diagnosis
detect biologically aggressive areas of disease
elucidate the “true” response to therapy
provide early signals of response or failure

10. Introduction…
IV) Investigation
• Early in the postoperative period, ideally within
48 hours, an MRI should be obtained
• Extra cranial staging is not performed routinely
b/c gliomas almost never met outside CNS
• The typical imaging appearance of a GBM is a
ring-enhancing or heterogeneously enhancing
lesion with vasogenic edema.
• Nearly all GBMs demonstrate contrast
enhancement.

12. V) Prognosis

13. Introduction…
VI) management options of GBM
• Standard treatment consists of maximal safe surgical resection
followed by RT(60Gy in 1.8-2Gy/≠) with concurrent
chemotherapy(TMZ) and subsequent adjuvant TMZ
chemotherapy and consideration for application of TT Fields
• Because of their infiltrative nature & proximity to critical
structures, complete surgical resection is very rarely possible,
but prognosis is improved in proportion to the degree of
completeness of excision.
• Surgery is essential to:
 confirm the diagnosis
 differentiate tumor subtypes
 define the grade
 For molecular profile of tumors evaluation

14. Introduction…

15. Patient positioning and simulation
• Patients are usually simulated after surgical
wound apposition is reasonably stable and free of
infection (commonly after 10-14 dys of surgery).
• The patient is positioned supine or prone
depending tumor location with arms at the sides.
• Immobilization is achieved with a thermoplastic
mask.
• Head frame is usually used for single-fraction
stereotactic radio surgery (SRS).

17. Patient positioning and simulation
• CT simulation to delineate gross tumor volume
GTV, CTV & PTV.
• Use spiral CT to plan with 1 to 3 mm slice
acquisition from the vertex through the mid
cervical spine region to allow :
sufficient anatomic areas for proper image fusion
generation of high-quality digitally reconstructed
radiographs (DRRs)
 to permit the introduction of noncoplanar beams

18. Patient positioning and simulation
• IV contrast for enhancing lesions used to
delineate the tumor volume/resection cavity.
• A previously obtained MRI image may be fused
with the CT images in the treatment planning
system to facilitate better target volume
delineation.
• Ideally, the slice thickness should match that of
the MRI used for fusion.
• Computerized treatment planning is then used to
generate radiation beam angles, blocks, and dose
distributions

19. Target volume
• Most malignant gliomas are unifocal at the time
of initial Dx, & after Rx the majority recur at or
within 1-2 cm of their original location
• In the past WBRT was advocated due to
infiltrative nature.
• WBRT is commonly recommended for patients
with multifocal tumors.
• After development of CT/MRI limited RT field
encompassing contrast enhancing lesion with
margin have been advocated

20. Target volume
• inclusion of all radiographic evidence of tumor
and associated edema with generous margins is
common practice in the design of treatment
portals.
• The extent of margin expansion remains a
controversial area, with considerable variance!

21. Target volume
• Common sense and practice dictates that these
CTV expansion margins should not traverse
anatomically discontinuous structures or include
areas unlikely to be infiltrated by tumor.
• Inclusion of the bony skull is unnecessary unless
direct tumor extension is suspected

22. Target volume
• For HGGs, especially GBM, T1 contrast-enhanced
sequences are used to define the GTV and the T2
or FLAIR sequences plus a margin to define the
microscopic disease extent or CTV, which reflects
the bulk of microscopic infiltration.
• To arrive at a PTV, both organ motion and setup
error must be taken into account(1-2mm).

23. Target volume
• Two major schools of thought (with numerous
institutional variations)that provide guidance for
the prescription of the radiation:
• RTOG
• EORTC

24. Target volume
• RTOG:
• RTOG approach is a biphasic technique that includes
an initial PTV (PTV1) followed by a second PTV
(PTV2) that represents the cone down.
• Postoperative MRI scans are used, and the PTV1
includes
• GTV1 - T2 or FLAIR changes
• CTV1- T1 & margin of 2 cm
• PTV1-further margin of 3-5mm and Rx with 46Gy in
2Gy/≠
• GTV2-T1-enhancing
• CTV2-margin of 2 cm & is Rx with additional 14Gy.

25. Target volume
• In contrast, the EORTC recommends a single-
phase technique using one treatment volume
throughout the course of therapy.
• GTV -postoperative enhancing T1 lesion
• CTV- 2- 3cm margins
• PTV-3-5 mm & is treated with 60 Gy.

26. Patient positioning and simulation

29. Target volume
• GTV: postoperative resection cavity, contrast
enhancement, or edema on T2/FLAIR
• CTV: GTV + 2 cm if edema on T2/FLAIR or 2.5 cm
if no edema with respect for natural boundaries
• PTV: CTV + 0.3 to 0.5 cm
• Adequate coverage of tumor volume may be
accompanied with 2 or more fields.

30. Target volume

31. RT dose & fractionation
• Conventional RT dose of 60Gy in 1.8-2Gy per
fraction
• The portal may be reduced after 50Gy (if the
initial volume was large) to encompass the
contrast enhancing volume with2-3cm margin
not included the edema
• Treatment should be delivered with multiple
fields to achieve homogeneity throughout the
volume & to spare dose to uninvolved brain
• Lateral opposed fields are used only when
extensive bilateral tumor involvement is present.

32. RT dose & fractionation
• 46 Gy in 2Gy/≠ to T2/FLAIR change
• Boost 14 Gy in 2 Gy/ ≠ to the resection cavity or
postoperative T1 contrast enhancement (GTV)
with a 2.0 cm margin for CTV and 0.3 to 0.5 cm
PTV

33. Treatment delivery and patient care
• During the first days of Rx, there may be an ↑ in
peritumoral edema, which may require
adjustment or introduction of steroid dosage to
prevent headache and vomiting.
• Antiemetics may also be required
• Rapid deterioration during treatment may lead to
discontinuation of radiotherapy
• If temozolomide is used, blood counts should be
checked weekly

34. Toxicities
• The response of intracranial tissues to radiation
has been classically divided into three phases
based on the timing of onset of symptoms:
Acute –with in 6 weeks
Subacute-6 wks to 6mon
 late-after 06 months to many yrs

35. Toxicities
a) Acute toxicities
• Transient worsening of pretreatment deficits may
develop during the course of treatment.
• These symptoms are believed to be the
consequence of a transient peritumoral edema.
• Persistent or refractory symptoms may be caused
by tumor progression, and repeat imaging while
under treatment may be indicated if the clinical
condition worsens despite steroids

36. Toxicities
• A) Acute toxicities:
• General symptoms such as fatigue, headache,
and drowsiness may be seen, especially in
individuals treated with large brain fields
• Nausea and vomiting independent of changes in
intracranial pressure may occur, particularly with
posterior fossa or brainstem irradiation.

37. Toxicities
b) Sub acute :
• Is attributed to changes in capillary permeability as
well as transient demyelination due to damage to
oligodendroglial cells
• Symptoms include headache, somnolence,
fatigability, and deterioration of pre-existing deficits,
usually respond to steroids.
• The main challenge is to distinguish the clinical and
imaging findings from tumor recurrence.
• The phenomenon of “pseudoprogression”
temporally fits within the subacute toxicity time
frame

38. Toxicities
c) Late sequelae:
• Late sequelae of radiotherapy appear from 6
months to many yrs following treatment and are
usually irreversible and progressive
• They are thought to be due to white matter
damage from vascular injury, demyelination, and
necrosis.

39. Toxicities
c) Late sequelae:
• The most serious late reaction to RT is radiation
necrosis, which has a peak incidence at 3 years.
• Radiation necrosis can mimic recurrent tumor :
clinically by the reappearance and worsening of :
initial symptoms
neurologic deficits
 imaging development of a progressive, irreversible,
enhancing mass with associated edema.
• PET, MR spectroscopy, and nuclear and dynamic CT
scanning procedures may aid in the differentiation of
radiation necrosis from recurrent tumor

40. Toxicities
c) Late sequelae:
• The best treatment for symptomatic necrosis is
control of symptoms with steroids followed by
surgical debulking.
• Given the central role of capillary leakage to
radiation necrosis, bevacizumab, has been tested
clinically as treatment for radiation necrosis and
has shown encouraging results.

41. OAR

42. OAR

43. Special considerations
• Elderly patients or patients with poor
performance status may be considered for
altered fractionation, including:
• 40 Gy/2.67 Gy/≠
• 37.5 Gy/2.5 Gy/≠
• 30 Gy/3 Gy/≠ (as whole-brain RT)

45. Thank you!