Transcript Slide 1

Implications for Patient Care and Tumor Treatment
WHO Grade Astrocytoma (Tatter, 2005)
WHO designation
criteria
pilocytic astrocytoma
astrocytoma
anaplastic
(malignant)astrocytoma
glioblastoma
WHO grade*
Kernohan grade*
St. Anne/Mayo grade
I
II
I
I, II
excluded
1
2
III
II, III
3
IV
III, IV
4
St. Anne/Mayo
no criteria fulfilled
one criterion: usually
nuclear atypia
two criteria: usually
nuclear atypia and mitosis
three or four
criteria:
usually the and/or necrosis
*The WHO and Kernohan systems are not criteria based. Thus, a given tumor may not fall under the same designation in all
three systems.
Glioblastoma: Characteristics
 Under the modified WHO classification, GBM differs
from anaplastic astrocytomas (AA) by the presence of
necrosis under the microscope. Variants of the tumor
include gliosarcoma, multifocal GBM, or gliomatosis
cerebri (in which the entire brain may be infiltrated
with tumor cells). These variants, however, do not alter
the prognosis of the tumor. Seldom do GBMs
metastasize to the spinal cord or outside the nervous
system.
Glioblastoma: Risk Factors
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Sex: male (slightly more common in men than women)
Age: over 50 years old
Ethnicity: Caucasians, Latinos, Asians
Having a low-grade astrocytoma (brain tumor), which occasionally
develops into a higher-grade tumor
 No links have been found between glioblastoma and smoking, diet,
cell phones, and electromagnetic fields (Zheng et al, 2001;
Huncharek et al, 2003; Inskip et al, 2001; Savitz et al, 1998)
 There has been a small link proposed between ionizing radiation
and glioblastoma (Ino et al, 2000)
 Some suggest a link between brain cancer and occupational
exposures in the work place (Navas-Acien et al, 2002)
Alkylating Agents: Mechanism
Attaches alkyl groups (small carbon compounds) to DNA bases. This
alteration results in the DNA being fragmented by repair enzymes in
their attempts to replace the alkylated bases. Alkylated bases prevent
DNA synthesis and RNA transcription from the affected DNA.
(2) Formation of cross-bridges, bonds between atoms in the DNA. In
this process, two bases are linked together by an alkylating agent that
has two DNA binding sites. Bridges can be formed within a single
molecule of DNA or a cross-bridge may connect two different DNA
molecules. Cross-linking prevents DNA from being separated for
synthesis or transcription.
(3) Induction of mispairing of the nucleotides leading to mutations. In a
normal DNA double helix, A always pairs with (is across from) T and
G always pairs with C. Alkylated G bases may erroneously pair with
Ts. If this altered pairing is not corrected it may lead to a permanent
mutation.
(1)
Carmustine
Image courtesy of www.wikipedia.com
Temozolomide
Image courtesy of www.wikipedia.com
Stupp et al, 2005, NEJM
Background
 Glioblastoma is the most frequent primary malignant brain tumor
 Median survival typically <12 months
 Standard therapy (U.S.)= Surgical resection + Radiotherapy +
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Carmustine (nitrosourea)
Meta-analysis (which included 37% of patients with more favorable
gliomas) based on 12 randomized trials found a 5% increase in survival
at 2 years with chemotherapy (Stewart et al, 2002)
Temozolomide depletes DNA repair enzyme O6-methylguanine-DNA
methyltransferase (MGMT; Yung et al, 2000)
Longer survival is associated with low levels of MGMT in tumor tissue
in glioblastoma patients receiving nitrosourea-based adjuvant
chemotherapy (Esteller et al, 2000)
Pilot Phase II Trial: demonstrated feasibility of concurrent
temozolomide admin with fractionated radiotherapy (Stupp et al,
2002)
Prognostic Factors (Gorlia et al, 2008)
 Location of the tumor (operable or inoperable)
 How much of the tumor volume can be safely removed (extent of
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surgical resection)
How much necrosis is present within the tumor as observed on
MRI imaging studies
Age of the patient
Patient's performance status : extent of neurological and
functional impairment
Mini-Mental State Examination (MMSE) score of 27 or higher
No corticosteroid treatment at baseline
http://www.eortc.be/tools/gbmcalculator
www.answers.com
WHO Performance Score
AKA the “ECOG score” (Oken et al, 1982):
• 0 - Asymptomatic (Fully active, able to carry on all pre-disease
activities without restriction)
• 1 - Symptomatic but completely ambulatory (Restricted in physically
strenuous activity but ambulatory and able to carry out work of a light
or sedentary nature. For example, light housework, office work)
• 2 - Symptomatic, <50% in bed during the day (Ambulatory and capable
of all self care but unable to carry out any work activities. Up and about
more than 50% of waking hours)
• 3 - Symptomatic, >50% in bed, but not bedbound (Capable of only
limited self-care, confined to bed or chair 50% or more of waking
hours)
• 4 - Bedbound (Completely disabled. Cannot carry on any self-care.
Totally confined to bed or chair)
• 5 - Death
Methods: Patient Selection
 Age: 18 to 70
 New diagnosis and histological confirmation of
glioblastoma
 Inclusion criteria: (1) WHO performance status of 2 or
less (2) absolute neutrophil ≥ 1500 per mm3 (3) platelet
≥ 100,000 per mm3 (4) serum creatinine ≤ 1.5 x ULN (5)
total serum bilirubin ≤ 1.5 x ULN (6) liver function < 3
x ULN
 Patients receiving corticosteroids received a stable or
decreasing dose for 14d prior to randomization
Methods: Study Design
 EORTC & NCIC conducted the trial
 Within 6 weeks after histological diagnosis, “randomly
assigned” eligible patients to control or treatment
group
 Stratification along: (1) WHO performance status (2)
previous de-bulking surgery (3) treatment center
(Pocock et al, 1975)
 Randomization procedure not described
 Assigned treatment was to begin within 1 week after
randomization
Methods: Control Group
Control:
 Radiotherapy: fractionated focal irradiation (2Gy per
fraction given 1x per day x 5 d/wk x 6wks) = 60Gy in
total
 Delivered to gross tumor volume +2-3 cm margin
 CT and 3-D planning system, linear accelerators with
nominal energy of 6MV+, quality assurance through
individual case review (Ataman et al, 2004)
Methods: Treatment Group
 Temozolomide: 75 mg/m2/day x 7 d (no more than
49d)
 4 week break
 6 cycles of adjuvant temozolomide:
 150 mg/m2 x 28d x 1 cycle
 200 mg/m2 x 28d x 5 cycles
 PCP prophylaxis (pentamidine or bactrim)
 Antiemetic prophylaxis (metoclopromide or 5-
hydroxytryptamine antagonist)
Methods
 Baseline examination: CT or MRI, Blood counts/chemistry,
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physical exam, MMSE, and QOL questionnaire (not specified)
Comprehensive evaluations 21-28d after radiotherapy and every 3
mo thereafter: (1) MMSE (2) QOL questionnaire (3) radiologic
assessment of the tumor
Adjuvant temozolomide: (1) monthly clinical evaluation (2) end
of cycle 3 (3) end of cycle 6
Tumor progression: (1) increase in tumor size by 25% (2)
appearance of new lesions (3) increased need for corticosteroids
(Macdonald et al, 1990)
When tumor progression occurred or after 2 years of follow-up,
patients were treated at the “investigator’s discretion;” type of
second line therapy was recorded but not included in the results
Hematologic Toxicity Criteria
Blood Element (Units)
Neutrophils (x 10(3)/µL)
Platelets (x 10(3)/µL)
Hemoglobin (g/dL)
CD4 count (per µL)
Lymphocytopenia (per µL)
Grade 1
1.5 to LLN
75 to LLN
10 to LLN
500 to LLN
800 to LLN
Grade 2
1.0 to 1.5
50 to 75
8.0 to 10.0
200 to 500
500 to 800
Grade 3
0.5 to 1.0
25 to 50
6.5 to 8.0
50 to 200
200 to 500
Grade 4
< 0.5
< 25
< 6.5
<50
<200
Grade 5
Death due to cytopenia
Death due to cytopenia
Death due to cytopenia
Death due to cytopenia
Death due to cytopenia
Common Toxicity Criteria, National Cancer Institute, Version 3.0 (December 12, 2003).
Methods: Statistical Analysis
 Primary endpoint: overall survival
 Secondary endpoints: (1) progression-free survival (2)
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safety (3) QOL
80% power at a significance of .05 to detect 33%
increase in median survival assuming 382 deaths
occurred
Intention-to-treat analysis
Toxic effects: separated by radiotherapy period and
adjuvant therapy period
QOL findings “not reported here” ?
Methods: Organization of the Trial
 Schering-Plough provided an “unrestricted
educational grant” and the study drug
 Schering-Plough was “not involved in trial design or
analysis”
 Histologic specimens were analyzed by a panel of
three neuropathologists in Europe, and one in Canada
 Medical writer assisted Dr. Stupp in the writing of the
article
Results
 Aug 2000-Mar 2002: 573 patients from 85 institutions
in 15 countries
 ~50% of patients were enrolled at 17 institutions
 Median time from diagnosis to the start of therapy was
5 weeks: Control (range 2-12.9 wks) Treatment (range
1.7-10.7 wks)
 37 (13%) patients prematurely discontinued
temozolomide due to toxic effects
Results
 Median survival benefit: 2.5 mos
 Two-year survival rate: 26.5% vs 10.4%
 Progression-free survival: 6.9 vs. 5 mos
 Hazard ratio adjusted by (1) extent of surgery (2)
WHO performance status (3) treatment center (4) age
(5) corticosteroid use at time of randomization (6) sex
(7) score on MMSE (8) tumor location
 Two sub-group exceptions to the benefit
demonstrated: (1) underwent biopsy (2) poor
performance status at study initiation
Results: Safety
 Severe Infection: 6 (2%) control and 9 (3%) in
treatment
 Moderate to Severe Fatigue: 74 (26%) in control and 94
(33%) in treatment
 Thromboembolic events: 16 (6%) in control and 12
(4%) in treatment
 Cerebral hemorrhage: 2 died in treatment group
 Pneumonia: 5 (2%) in control and 3 (1%) in treatment
 Opportunistic infections: 1 in control 1 in treatment
Results: Disease Progression
 When disease progression occurred, further treatment
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was at “physician’s discretion”
At the cutoff date, 94% (control group) and 85%
(treatment group) had progression
23% in both groups underwent a second surgery
72% (control group) and 58% (treatment group)
received salvage chemotherapy
Salvage chemotherapy: temozolomide in 60% of
control and 25% of treatment
Response to salvage chemotherapy was not recorded
Discussion
 Trial not designed to parse out the effects of
concomitant therapy versus adjuvant therapy
 Temozolomide given concomitantly for several
reasons: (1) daily low dose allows for doubling by a
factor of 2 in dose intensity (2) continuous
administration depletes MGMT (3) synergy between
temozolomide and radiotherapy observed in vitro (4)
to ensure sufficient exposure to the drug, adjuvant
therapy was included following radiotherapy
Limitations: Study Design
 Secondary end points: Quality of life?
 “Clinically meaningful outcomes?”
 Randomization procedure not explained; possible
introduction of bias
 Blinding
 Length of drug administration
 Tumor location? Resectable volume? Necrosis initially
observed?
 Effects on salvage therapy users
Critique
 Ghost writer? (NYTimes, Aug 2009)
 Industry influence? (starting treatment early vs. rescue
treatment??)
 Cost-effectiveness versus gliadel wafers? (Garside et al,
2007; NICE)
References
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Esteller M, Garcia-Foncillas J, Andion E, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating
agents. N Engl J Med 2000;343:1350-1354.
Zheng, T, Cantor KP, Zhang Y, et al. (2001). "Risk of brain glioma not associated with cigarette smoking or use of other tobacco products in
Iowa". Cancer Epidemiol Biomarkers Prev 10: 413–4.
Huncharek M, Kupelnick B, Wheeler L (2003). "Dietary cured meat and the risk of adult glioma: a meta-analysis of nine observational
studies". J Environ Pathol Toxicol Oncol 22: 129–37.
Inskip PD, Tarone RE, Hatch EE, et al. (2001). "Cellular-telephone use and brain tumors". N Engl J Med 344: 79–86.
Savitz DA, Checkoway H, Loomis DP (1998). "Magnetic field exposure and neurodegenerative disease mortality among electric utility
workers". Epidemiology 9: 398–404.
Yung WK, Albright RE, Olson J, et al. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first
relapse. Br J Cancer 2000;83:588-593
Stupp R, Mason WP, van den Bent MJ, et al. (2005). "Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma". NEJM
352 (10): 987–996.
Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of eortc and ncic trial T Gorlia,
M Vandenbent, M Hegi, R Mirimanoff, M Weller, J Cairncross, E Eisenhauer, K Belanger, A Brandes, A Allgeier The Lancet Oncology (2008)
Volume: 9 Issue: 1 Pages: 29-38