12. HOW TO TREAT - SECONDARIES
Depends on Primary cancer and its extent / control
Depends on patient fitness and wishes
Can occasionally debulk and give post op
radiotherapy, or radiotherapy alone (20Gy in 5#)
15. TIMING OF CHEMOTHERAPY
Adjuvant
After surgery or radiation
Defined number of cycles
Aim
prolong time to recurrence
Recurrence
Number of cycles limited by side effects
Aim
improve symptoms, quality of life and slow progression
16. A BIT OF HISTORY..
Surgery and radiation mainstays of treatment (and
still are)
Chemotherapy options
PCV standard of care for many years
Procarbazine
Carmustine (BCNU)
Vincristine
Significant side effects
Single agent nitrosurea(lomustine/carmustine) equivalent
17. CHALLENGES TO TREATMENT
Biologically aggressive
• Most brain cancer are
unresponsive to
chemotherapy
Drug delivery
Blood brain barrier
Toxicity to normal brain
Infiltration of malignant
cells into brain
parenchyma
18. How to overcome BBB ???
Newer delivery methods include:
Interstitial chemotherapy uses disc-shaped polymer wafers (known as
Gliadel wafers) soaked with carmustine, the standard
chemotherapeutic drug for brain cancer.
Intrathecal chemotherapy delivers chemotherapeutic drugs directly into
the spinal fluid.
Intra-arterial chemotherapy delivers high-dose chemotherapy into
arteries in the brain using tiny catheters.
Convection-enhanced delivery (CED) involves placing catheters into
the brain tumor or nearby brain tissue to deliver slowly and
continuously a cancer drug over several days
http://www.umm.edu/patiented/articles/how_radiotherapy_used_treating_brain_tumors_000089_10.htm#ixzz256vtlVt
R
19. GLIADEL WAFERS
Gliadel wafers at time of surgery (carmustine soaked) in
completely resected high grade glioma (3 or 4)
The surgeon implants the wafer directly into the
surgical cavity after a tumor is removed.
21. Standard ones include:
Temozolomide (Temodar)
-Taken oral
-First approved in 1999 for adult patients with anaplastic astrocytoma that did
not respond to other treatments.
-In 2005, it was approved for use during and after radiation therapy for patients
newly diagnosed with glioblastoma multiforme.
-Adverse effects: Relatively minor, but may include constipation, nausea and
vomiting, fatigue, and headache.
23. Temozolomide 75 mg/m2 po qd for 6 weeks,
then 150–200 mg/m2 po qd d1–5 every 28 days for 6 cycles
Focal RT daily — 30 x 200 cGy
Total dose 60 Gy
TMZ/RT*
Adjuvant TMZ
Weeks6 10 14 18 22 26 30
RT Alone
R
STUPP TREATMENT SCHEMA
0
*PCP prophylaxis was required for patients receiving TMZ during the concomitant phase.
Concomitant
25. Carmustine (BCNU, BiCNU)
-Carmustine is used to treat many types of brain tumors, including
glioblastoma, medulloblastoma, and astrocytoma.
-Administered IV or delivered through a wafer implant (Gliadel),
which is surgically placed into the brain cavity after tumor removal.
-Adverse effects
-Intravenously: Nausea and vomiting, fatigue, respiratory
problems and pulmonary fibrosis, bone marrow impairment.
-Delivered through a wafer: Seizures and cerebral infection
26. PCV Drug Regimen
-PCV is an abbreviation for a chemotherapy regimen that combines
procarbazine (Matulane), lomustine (CCNU), and vincristine (Oncovin).
-PCV is commonly used to treat oligodendrogliomas and mixed
oligoastrocytomas.
-Procarbazine and lomustine are taken by mouth. Vincristine is given by
either injection or IV.
-Adverse effects:
Drop in blood cell counts, nausea and vomiting, constipation,
fatigue, and mouth sores.
Procarbazine can cause high blood pressure when taken with
foods high in tyramine. Patients should avoid foods such as
beer, red wine, cheese, chocolate, processed meat, yogurt,
and certain fruits and vegetables.
27. Platinum-Based Drugs
-Cisplatin (Platinol) and carboplatin (Paraplatin)
-Used to treat glioma, medulloblastoma, and other types of brain
tumors.
-Delivered by IV.
-Adverse effects:
Nausea and vomiting
Carboplatin can cause alopecia
Cisplatin can cause muscle weakness.
28. Other Chemotherapy Drugs
Researchers are investigating whether drugs used to treat other
types of cancer may have benefits for brain tumors. These drugs
include:
- Tamoxifen (Nolvadex) and paclitaxel (Taxol), which are used to
treat breast cancer
- Topotecan (Hycamtin), which is used to treat ovarian and lung
cancers
- Vorinostat (Zolinza), which is approved for treatment of cutaneous
T-cell lymphoma
-Irinotecan (Campath) is another cancer drug that is being studied in
combination treatment.
http://www.umm.edu/patiented/articles/how_radiotherapy_used_treating_brain_tumors_000089_10.htm#ixzz256w
UbUkK
30. -Targeted therapies work on a molecular level by blocking specific
mechanisms associated with cancer cell growth and division.
-less severe side effects.
Promising targeted therapies for brain tumors include:
1. Tyrosine kinase inhibitors
-It block proteins involved in tumor cell growth and production.
-Drugs that specifically target epidermal growth factor receptors (EGFR) are a type
of tyrosine kinase inhibitor of special interest in brain tumor research.
-These drugs include erlotinib (Tarceva), imatinib (Gleevac), and gefitinib (Iressa).
31. 2. Farnesyl protein transferase inhibitors
Tipifarnib (Zarnestra) and lonafarnib (Sarasar)
-These drugs target a protein involved in the functioning of the cancer-
causing Ras protein.
-Lonafarnib is being studied in combination with temozolomide, and
tipifarnib in combination with radiation therapy.
3. MTOR inhibitors
-Everolimus (RAD-001) is being studied for glioblastoma multiforme and
astrocytoma.
-Everolimus is related to rapamycin (Siroliumus) and tacrolimus (Prograf),
which are also being investigated for brain tumor treatment.
-These drugs are commonly used to suppress the immune system to
prevent rejection after organ transplantation.
www.umm.edu/patiented/articles/how_radiotherapy_used_treating_brain_tumors_000089_10.htm#ixzz256wfm64B
32. 4. Anti-angiogenesis drugs:
Bevacizumab (Avastin)
- It is being studied in combination with irinotecan for treatment
of recurrent malignant gliomas.
Cediranib (Recentin, AZD2171)
- It is another VEGF inhibitor being investigated for
glioblastoma treatment.
34. BEVACIZUMAB (AVASTIN)
To date mainly investigated in Phase II trials
Usually in combination with irinotecan chemotherapy
No trials have demonstrated a survival benefit
Side effects include
Hypertension (9%)
Delayed wound healing (2%)
Bowel perforation (2%)
Intracranial haemorrhage (2%)
Venous and arterial clots (4%)
35. BEVACIZUMAB IRINOTECAN IN RECURRENT
GBM
Phase II study in 167
patients
Friedman HS, et al. JCO 2009
Bevacizumab
(n = 85)
Bevacizumab
+
Irinotecan
(n = 82)
Response
%
28.2 37.8
6-mo PFS
%
42.6 50.3
Survival
(months)
9.2 8.7
37. Phase III Trials of Bevacizumab in newly
diagnosed GBM
AVAGLIO[1]
Newly diagnosed GBM
(planned N = 920)
Placebo q2w +
standard RT (60 Gy
D1-5) x 6 wks + TMZ
75 mg/m2 PO/day for
6 wks then 150-200
mg/m2 Days 1-5 of
each 6 x 4-wk cycle
until progression
Bevacizumab
10 mg/kg q2w +
standard RT (60 Gy
D1-5) x 6 wks + TMZ
75 mg/m2 PO/day for
6 wks then 150-200
mg/m2 Days 1-5 of
each 6 x 4-wk cycle
until progression
1. ClinicalTrials.gov. NCT00943826. 2. ClinicalTrials.gov. NCT00884741.
Newly Diagnosed GBM
≥ 18 years; KPS 70% to 100%
Standard RT + concurrent TMZ
(Planned N = 942)
4 wks after
chemoRT:
Adjuvant TMZ 200
mg/m2 D1-5 Q28D for
up to 12 courses +
placebo
Wk 4 of chemoRT:
Bevacizumab q2w,
continuing until
completion of adjuvant
TMZ
4 wks after chemoRT:
Adjuvant TMZ 200
mg/m2 Days 1-5 Q28D
for up to 12 courses +
placebo
RTOG 0825[2]
38. RANDOMISED PHASE II STUDY OF
CARBOPLATIN AND BEVACIZUMAB IN
RECURRENT GLIOBLASTOMA (CABARET)
IN patients of recurrent glioblastoma post radiation and
temozolomide
Bevacizumab carboplatin
Closed to accrual
Results awaited
39. ANGIOGENESIS-TARGETING AGENTS FOR
GLIOBLASTOMA
Target Agent Disease Setting Study Phase
Integrins Cilengitide nGBM
rGBM
Phase III
Phase I/II
Angiopoietin/Tie 2 CVX-060 rGBM Phase I/II
VEGF VEGF-trap
(aflibercept)
VEGFR TKIs
(cabozantinib,
cediranib, axitinib,
pazopanib)
Bevacizumab +
strategies
rGBM
nGBM
rGBM, nGBM
nGBM, rGBM
Phase II
Phase I
Phase I, II, III
Phase I, II, III
Endothelial cell
proliferation
Metronomic
temozolomide
nGBM, rGBM Phase II, III
ClinicalTrials.gov.
40. Wick W, et al Neuro-Oncol. 2011
GENETIC TARGETS IN GLIOBLASTOMA
EGFR, mutated/
amplified in 45%
HER2
mutated in 8%
PDGFRα,
amplified in 13%
MET,
amplified in 4%
Proliferation,
survival,
translation
FOXO,
mutated in 1%
NF1, mutated/
deleted in 18%
RAS,
mutated in 2%
PI3K,
mutated in 15%
PTEN, mutated/
deleted in 36%
AKT,
amplified in 2%
SRC
SRC
SRC
SRC
44. Progress Against Brain Cancer
2000–Present
2003: Chemotherapy "wafer" active against
malignant gliomas
45. Progress Against Brain Cancer
2000–Present
2005: MGMT gene alteration predicts response to
chemotherapy
2005- 2008: Researchers begin mapping the
genome of glioblastoma
46. Progress Against Brain Cancer
2000–Present
2006: Genetic mutations affect survival for
oligodendroglioma
2006: Chemically "illuminating" glioma tumors
during surgery postpones recurrence
2006: Molecular sub-classification of high-grade
gliomas predicts prognosis
47. Progress Against Brain Cancer
2000–Present
2008: Bevacizumab (Avastin) receives FDA
approval for glioblastoma
48. Progress Against Brain Cancer
2000–Present
2009: Gene mutations linked to tumor
aggressiveness
49. Progress Against Brain Cancer
2000–Present
2010: Nine-gene test can predict glioblastoma
outcome
50. Progress Against Brain Cancer
Five-Year Survival
20
22
24
26
28
30
32
34
36
38
40
1975
1977
1979
1981
1983
1985
1987
1989
1991
1993
1995
1997
1999
2001
2003
2005
2007
Year of Diagnosis
%ofPatientsSurvivingFiveYears
Source: National Cancer Institute
51. CONCLUSION
Current standard of care
TMZ + RT followed by 6 months of TMZ
Recurrence
Treatment options unsatisfactory
TMZ / nitrosurea / bevacizumab
Involvement in clinical trials encouraged
Multiple new therapies under development
CBTRUS, Central Brain Tumor Registry of the United States; CNS, central nervous system.
Anti-angiogenesis drugs block molecules involved with the growth of blood vessels that feed the tumor (a process called "angiogenesis," which is particularly important in the growth of glioblastomas.) These drugs starve tumors of vital nutrients and oxygen. Bevacizumab, which targets vascular endothelial growth factor (VEGF), a specific angiogenesis growth factor
