harmesh naik, md. · anaplastic oligodendroglioma a recent phase iii study compared radiation...
TRANSCRIPT
Harmesh Naik, MD.
June 22, 2011
Marriott Series CME symposium
Primary brain tumors
Discussion is limited to Primary brain
tumors
Interesting facts
Annual incidence: 14 per 100,000
population
Most common tumors are:
Meningiomas 27%
Glioblastomas 23%
Epidemiology
Gender: Slightly more common in men
Age: Bimodal distribution with tow
peaks
Small peal in children
Second peak between 75-84 years
Risk factors
Genetic factors: plays a minor role
Hereditary: Less than 5%
Increased risk in
Tuberous sclerosis
Neurofibromatosis
Turcot syndrome
Li-Fraumeni syndrome
Genetics
Loss of heterozygosity (LOH): Loss of
function of one copy of a gene where one
copy was already inactivated
High grade gliomas
LOH on 9p
LOH on 10q
P16 deletions
Low grade gliomas
Fewer molecular abnormalities
Genetics
Oligodendrogliomas:
Better prognosis with
LOH on 1p
LOH on 19p
Environmental factors
Prior brain radiation is a risk
Not clear or not associated
Smoking
Alcohol use
Cell phone use
Symptoms
General: Headaches, nausea, vomiting,
seizures, mental status changes
Site specific: Loss of functions,
paralysis, speech problems, visual filed
defects, etc
Diagnosis:
Radiology:
MRI or contrast CT
Contrast enhancing mass with edema
About 5% are multi-focal
Low grade gliomas can be non enhancing
PET scan: May not be as accurate as
MRI
Biopsy
Diagnosis by biopsy is preferred.
Stereotactic biopsy can be used for
lesions that are difficult to reach and
resect.
Pathology
Grade I to IV
Low grade:
Astrocytoma
Oligodendroglioma
Ependymomas-high recurrence rate
High grade:
Glioblastoma multiforme
Anaplastic astrocytoma
Anaplastic Oligodendroglioma
Staging
No uniform staging system
Prognostic factors
Pathologic grade
High grade - poor prognosis
Anaplastic oligodendrogliomas and
oligoastrocytomas -better prognosis than
anaplastic astrocytomas.
Age
Older age – worse prognosis
Genetic defects
1p and 19q LOH- better prognosis
Prognosis: Median survival
Histology Years Comment
Anaplastic astrocytoma 3 Surgery + RT + CT
Glioblastoma 1 Surgery + RT + CT
Low grade astrocytoma 5-10
Low grade oligodendroglioma 16
Low grade glioma 5 with age >40 yrs
Secondary brain mets 4-6 months
Supportive care
Anti-consultants
Given to those with seizures (25%)
Traditional agents: Phenytoin,
Carbamazepine, Phenobarbital
Newer anti-convulsants may have lesser
cognitive side effects (Keppra, Topamax
etc)
Prophylactic use: Not well proven
Steroids
Reduce brain edema –reduce mass effect
Prompt relief of symptoms
Dexamethasone – first choice – 16 mg/day
Taper as tolerated once definitive treatment
is started
Long term side effects
Definitive therapy
Multi-disciplinary therapy
Surgery
Radiation
Chemotherapy
Generally non curative
Surgery
Surgical removal is recommended for most
types of brain tumors in most locations.
Surgical removal should be as complete as
possible within the constraints of
preservation of neurologic function
Further discussion by another panel
speaker
Radiation
Radiation therapy has a major role in the
treatment of patients
Further discussion by another panel
speaker
Local chemotherapy
Local chemotherapy with a nitrosourea
applied to a polymer placed directly in
the brain during surgery has been
shown to be a safe modality and is
under clinical evaluation
Best discussed by a neuro-surgeon
Chemotherapy (Systemic)
Limited but measurable role to play
Sensitivity depends on histology of
tumor
Role of Chemotherapy
Low grade astrocytoma: No major role
Oligodendroglioma: Chemo-sensitive
Anaplastic or high grade tumors:
Important role
Timing
Adjuvant chemotherapy: for initially
diagnosed – given after surgery –
concurrent with radiation
Palliative Chemotherapy: for recurrent
or progressive cancer
Chemotherapy: Results
May prolong survival in patients with
some tumor types
Has been reported to lengthen disease-
free survival
Used in patients with
Gliomas,
Medulloblastoma,
Some germ cell tumors.
Agents - regimens
Temozolamide: Most active and most
commonly used agent currently
PCV (Procarbazine, CCNU, Vinblastine)
has been used in past
BCNU – no longer used commonly
Bevacizumab, Irinotecan – newer agents
Glioblastoma Multiforme
Radiation therapy and concurrent
chemotherapy (Current standard)
Based on EORTC 26981) : A randomized
study
Stupp, R et al. N Engl J Med 2005; 352:987-996
Design
EORTC 26981 trial
Arm I
RT
Arm II
RT + CT
Details of study arms
Arm I: Radiotherapy 5
days a week for 6 weeks.
Arm II: Radiotherapy +
concurrent oral
Temozolomide daily for 6
weeks Adjuvant oral
Temozolomide alone on
days 1-5 every 28 days for
6 courses beginning 4
weeks after completion of
radiotherapy.
RT + TEM
6 weeks
TEM
6 courses
Temozolamide (TMZ) details
• Concomitant chemotherapy: Temozolomide 75 mg/ m2/ day, given 7 days per week, start day 1 of RT until the last day of radiotherapy, but for no longer than 49 days.
CT-RT
• Then 4-week break Rest
•Then up to six cycles of adjuvant Temozolomide standard 5-day schedule every 28 days.
The dose was 150 mg/ m2/ day, for the first cycle and was increased to 200 mg/ m2/ day, beginning with the second cycle, so long as there were no hematologic toxic effects.
CT
Follow up
Anti PCP prophylaxis
Lymphocytopenia with a possible increased risk of opportunistic infections.
Temozolomide group were to receive prophylaxis against Pneumocystis carinii pneumonia
Inhaled Pentamidine
or
Oral trimethoprim–sulfamethoxazole during concomitant treatment with radiotherapy plus
temozolomide.
Antiemetic prophylaxis
Recommended before the initial doses
of concomitant Temozolomide
Required during the adjuvant five-day
courses of temozolomide.
Results
Study demonstrated a statistically
significant increase in median survival of 3
months in the combination-treated group
(12.1 months versus 14.6 months)
The 2-year survival rate was 26.5% in the
combination group compared with only
10.4% in the radiation-only group.
The treatment is relatively safe and well
tolerated.
Median Survival
12.1
14.6
0
2
4
6
8
10
12
14
16
Months
RT
RT + CT
Survival in %
10.4
26.5
0
5
10
15
20
25
30
2 year
RT
RT + CT
Standard of care
EORTC regimen is considered standard of care by most for high grade GBM
Sequential CT-RT
Interesting concept
NOA-04: A randomized phase III trial of sequential radio chemotherapy of anaplastic glioma with Procarbazine, Lomustine, and Vincristine or Temozolomide.
CONCLUSIONS: Initial radiotherapy or chemotherapy achieved comparable
results in patients with anaplastic gliomas.
TMZ is less toxic than PCV
IDH1 mutations may indicate improved prognosis
Wick W et al: JCO 2009 Dec 10;27(35):5874-80
Anaplastic Oligodendroglioma
Patients with an allelic loss at 1p and
19q have a higher than average
response rate to PCV chemotherapy.
Cairncross JG et al.: J Natl Cancer Inst 90 (19): 1473-9, 1998.
Brandes AA et al.: Phase II trial Cancer 101 (9): 2079-85, 2004.
Anaplastic Oligodendroglioma
A recent phase III study compared
radiation therapy alone with
chemotherapy plus radiation therapy.
Progression-free survival was increased
but overall survival was not.
van den Bent MJ et al.: EORTC phase III trial. J Clin Oncol 24 (18): 2715-22, 2006.
TMZ in Low-grade oligodendroglial tumors
(LGOT)
Temozolomide (TMZ) as initial treatment
TMZ was administered at the starting
dose of 200 mg/m2/d for 5 days,
repeated every 28 days
Predictive value of chromosome 1p
deletion on the radiologic response
TMZ in Low-grade oligodendroglial tumors
(LGOT)
Loss of chromosome 1p was associated with objective tumor response
The median time to maximum tumor response was 12 months (range, 5 to 20 months).
Myelosuppression was the most frequent side effect, with grade 3 to 4 toxicity in 8% of patients.
Clinically, 51% of patients improved, particularly those with uncontrolled epilepsy.
The objective radiologic response rate was 31% (17% partial response and 14% minor response), whereas 61% of patients had stable disease and 8% experienced disease progression.
Hoang-Xuan K et al.: J Clin Oncol 22 (15): 3133-8, 2004.
PCV in Low-grade oligodendroglial tumors
Successful treatment of low-grade oligodendroglial tumors with a chemotherapy regimen of procarbazine, lomustine, and vincristine
Anaplastic oligodendroglioma (OD) tumors, especially those with the combined loss of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q), are sensitive to chemotherapy
Three of five patients with recurrent tumors responded.
Thirteen of the 16 newly diagnosed patients showed evidence of response.
The median time to disease progression in this group was > 24 months.
Stege EM, et al.: Cancer 103 (4): 802-9, 2005.
TMZ in recurrent glioma
Multicenter Phase II Trial of Temozolomide in Patients With Anaplastic Astrocytoma or Anaplastic Oligoastrocytoma at First Relapse
Progression-free survival (PFS) at 6 months, 46%
The median PFS was 5.4 months, and PFS at 12 months was 24%. The median overall survival was 13.6 months
The 6- and 12-month survival rates were 75% and 56%, respectively.
The objective response rate determined by independent central review of gadolinium-enhanced magnetic resonance imaging scans of the ITT population was 35% (8% complete response [CR], 27% partial response [PR]), with an additional 26% of patients with stable disease (SD).
The median PFS for patients with SD was 4.4 months, with 33% progression-free at 6 months
Maintenance of progression-free status and objectively assessed response (CR/PR/SD) were both associated with health-related quality-of-life (HQL) benefits.
Adverse events were mild to moderate, with hematologic side effects occurring in less than 10% of patients.
W.K. Alfred Yung et al: JCO Vol 17, Issue 9 (September), 1999: 2762
Bevacizumab in recurrent glioma
FDA Approved
An option for patients with recurrent glioma
Two phase II trials – Bevacizumab with Irinotecan
Response rate 26%-35%
PFS at 6 months up to 29 - 50%
No superiority of combination containing Bevacizumab over single agent yet
Optimal role of Bevacizumab is yet to be established
Friedman et al: JCO 2009: 4733 and Kreisl TN et al JCO 2009: 740.
Novel approaches
Novel biologic therapies under clinical evaluation for patients with brain tumors: Dendritic cell vaccination
Tyrosine kinase receptor inhibitors
Farnesyl transferase inhibitors
Viral-based gene therapy
Oncolytic viruses
Epidermal growth factor receptor inhibitors
Vascular endothelial growth factor inhibitors
Antiangiogenesis agents.
Other sites
The experience with chemotherapy for
primary spinal cord tumors is rare; no
reports of controlled clinical trials are
available for these types of tumors.
Additional reading
Wen PY et al: New England Journal of
Medicine: 359: Review: 492-506. July 21,
2008.
Theeler BJ et al: Current treatment options
in Neurology: April 16, 2011 – online.
Mason WP wt al: Current oncology: 14(3):
110-117.
Chamberlain MC et al: Clinical medicine
insights: Oncology: 2011: 5: 117-129.