harmesh naik, md. · anaplastic oligodendroglioma a recent phase iii study compared radiation...

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.