Download Low-grade Gliomas - American Brain Tumor Association

Low Grade Tumors: Update in Treatment and Care
Jeffrey Raizer, MD
Professor of Neurology
Director, Medical Neuro-Oncology
Northwestern University, Feinberg School of Medicine
Chicago, IL USA
Classification and Grading
• World Health Organization (WHO) Classification System
– Released in 1993; updated in 2007
– Tumors classified by cell origin and level of aggression
(Grades I–IV)
Grade
Histology
Proportion of
All Gliomas2
I
Pilocytic astrocytoma
5.2%
II
Well-differentiated
astrocytoma
1.8%
III
Anaplastic
astrocytoma
13.8%
IV
Glioblastoma
multiforme
53.9%
1. Kleihues, et al. Brain Pathol. 1993;3(3):255-268.
2. 2012 CBTRUS Report.
3. Wick, et al. J Clin Oncol. 2009;27:5874-5880.
Astrocytoma
Normal
Oligodendroglioma
Low-grade Gliomas: Epidemiology
• Tumors of young adulthood
– Median age 35 years
• Slight male preponderance
– 55 to 65% male
• Supratentorial in adults
• Symptoms
– Seizures
70-90%
– MS Changes
3-30%
– Increase ICP
10-40%
– Focal Deficits
2-30%
Clinical Prognostic Factors
•
•
•
•
•
•
•
•
Age: survival decreases with increasing age, > 40
KPS; presence of neurologic deficits
MS changes
Seizures isolated Sx and length of Sx
Size of tumor > 6 cm
Contrast enhancement
Crossing of the CC
Histology: Astrocytoma vs. Oligodendroglioma
Tumor Prognostic Factors
•
•
•
•
1p and 19Q status for Oligodendrogliomas
MGMT
IDH 1/2
G-CIMP-hypermethyation phenotype
Surgery
• Alleviation of neurological deficits
• Required for pathologic confirmation, molecular
and genetic profile
• Minimize residual tumor
– 13-86% malignant transformation (2-5 years)e
• Location
• Size/Extent
• Optimize surgery: f-MRI, DTI and Intraoperative
mapping
> 90% EOR
< 90% EOR
5- and 8-year OS rates of 97% and 91%
5- and 8-year OS rates of 76% and 60%
Median survival
Biopsy: 5.9 years
Resection: NR
Grade II astrocytomas median survival
Biopsy: 5.6 years
Resection: 9.7 years
Malignant transformation was more common in biopsy group (56% vs 37%).
Radiotherapy: Randomized Trials Dose
A randomized trial on doseresponse in radiation therapy of
low-grade cerebral glioma:
European Organization for
Research and Treatment of
Cancer study 22844.
Karim et al. Int J Radiat Oncol Biol Phys. 1996 Oct
1;36(3):549-56.
– 45 Gy vs 59.4 Gy
• 5 yr OS 58% vs 59%
• 5 yr PFS 47% vs 50%
• Extent of resection
important
• Decrease in QOL in 59.4
cGy group
Prospective randomized trial of lowversus high-dose radiation therapy in
adults with supratentorial low-grade
glioma: initial report of a North Central
Cancer Treatment Group/Radiation
Therapy Oncology Group/Eastern
Cooperative Oncology Group study.
Shaw et al. J Clin Oncol. 2002 May 1;20(9):2267-76
•50.4 Gy vs 64.8 Gy
–
–
–
–
2 yr OS: 85% vs 94%
5 yr OS 72% vs 65%
5 yr PFS 55% vs 52%
Neuro-toxicity: 2% vs 10%
Radiotherapy: Randomized Trial Timing
Randomized trial on the efficacy of radiotherapy for cerebral
low-grade glioma in the adult: European Organization for
Research and Treatment of Cancer Study 22845 with the
Medical Research Council study BR04: An interim analysis.
Observation vs RT (54 Gy)
5 yr OS 55% vs 63%
5 yr PFS 37% VS 44%
MTP 3.4 yrs vs 4.8 yrs
Karim et al. Int J Radiat Oncol Biol Phys 52, 316-324, 2002
Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and
oligodendroglioma in adults: the EORTC 22845 randomised trial.
Van Den Bent et al. Lancet. 2005 Sep 17-23;366(9490):985-90.
Overall survival
Progression free survival#
Median
% alive at 5
years
Median
5 yr progression
free survival
7.35
(6.14, 8.91)
65.65
(57.79, 73.50)
3.37
(2.89, 4.35)
34.61
(26.74, 42.47)
Immediate radiotherapy
7.22
95% CI
(6.44, 8.62)
68.44
(60.65, 76.23)
5.34
(4.61, 6.30)
55.00
(46.70, 63.30)
No early radiotherapy
95% CI
Radiotherapy: Conclusions from randomized studies
• Lower doses of radiotherapy are as effective as higher
doses for control of low-grade glioma
• Radiotherapy for low-grade gliomas can safely be
delayed until evidence of tumor progression
– Recurrence or increase in symptoms
– Assess by prognostic factors
Chemotherapy
• Issues
–
–
–
–
Slow growing tumors
Drug penetration
Systemic toxicity
Response criteria
Chemotherapy?
Randomized Trial of Radiation Therapy Plus Procarbazine, Lomustine, and Vincristine
Chemotherapy for Supratentorial Adult Low-Grade Glioma: Initial Results of RTOG 9802.
Shaw et al. J Clin Oncol 2012, 30:3065-3070.
• Favorable pts (< 40 yrs, GTR): observed
• Unfavorable pts (> 40 yrs, STR/Bx): RT +/- PCV x 6 cycles
– Stratified by age, histology, KPS, +/- enhancement
• 251 eligible patients were accrued from 1998 to 2002.
• Results:
– Arm 1
– Arm 2
– Arm 3
5 yr PFS
48%
42%
60%
5 yr OS
93%
62%
71%
Results
•
•
•
•
•
RT/PCV
vs. RT alone
mOS
NR (> 8 yrs)
vs. 7.5 yrs
5 yr OS 72%
vs. 63%
mPFS
NR (> 6.1 yrs)
vs. 4.4 yrs
5 yr PFS 63%
vs. 46%
For 2 yr survivors: Probability of another 5 yrs of
survival was 74% vs. 59%
Shaw et al. JCO 2012;30:3065-3070
Progression-free survival for all patients from date
of registration/random assignment.
Progression-free survival for patients
surviving to 2 years.
Shaw et al. JCO 2012;30:3065-3070
Overall survival for all patients from date of
registration/random assignment.
Overall survival for patients surviving to 2 years.
Phase III study of radiation therapy (RT) with or without
procarbazine, CCNU, and vincristine (PCV) in low-grade glioma:
RTOG 9802 with Alliance, ECOG, and SWOG.
Buckner et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 2000)
• Median follow up is 11.9 years.
– RT + PCV vs. RT alone
– mOS (13.3 vs. 7.8 years, p=0.03; HR=0.59)
– mPFS (10.4 vs. 4.0 years, p=0.002; HR=0.50)
– 5 and 10 year OS are 73% vs 64%, and 62% vs 41%.
– A or A-dominant OA histology was prognostic for
decreased OS and PFS.
Phase 2 study of temozolomide-based chemoradiation therapy
for high-risk low-grade gliomas: preliminary results of
radiation therapy oncology group 0424.
Int J Radiat Oncol Biol Phys. 2015 Mar 1;91(3):497-504
• RT (54 Gy) +TMZTMZ x 12
– Patient must have at least three of the following risk factors:
• Age ≥ 40, tumor ≥ 6 cm, tumor crosses midline
• Tumor subtype of astrocytoma (astrocytoma dominant)
• Preoperative Neurological Function Status > 1
•
•
•
•
•
129 evaluable patients.
Median follow-up of 4.1 years
3-year OS rate was 73.1%
Median survival time NR.
3-year progression-free survival was 59.2%.
Conclusions: Low-grade Gliomas
 High risk patients (< GTR or > 40 years of age) PCV + RT
prolongs both OS and PFS compared with RT alone.
 Unknowns
 Low Risk patients?
 Different risk factors
 Optimal chemotherapy or regimen
 TMZ less toxic than PCV
 How long to treat
 Does chemotherapy alter natural progression of LGG
 Is RT or chemotherapy better?
 RT + Chemo TMZ vs sequential treatment?
 Molecular factors?
 MGMT
 IDH
Which is better: PCV or TMZ?
• What does “better” mean?
– Better for Whom?
• 1P/19Q Deleted or non-deleted tumors
–
–
–
–
–
–
Longer survival
Longer progression free survival
Higher response rate
Maintain better QOL while on treatment
Easier administration
Less toxic
• Does greater toxicity merit use by increased OS or PFS
Which is better: PCV or TMZ?
• What does “better” mean?
–
–
–
–
Less toxic
Easier administration
Higher response rate
Longer survival
– Level 1 data in co-deleted patients RT + PCV
– No Level 1 data with TMZ
• Suggestion PCV is better
• Worth added toxicity??
TMZ!
PCV?
31 F Recurrent
LG Oligo
1p deletion
S/P PCV x 5
53 M with Grade II
Astrocytoma
Temodar x 8
12/10/01
9/4/0
2
Targeted Molecular Therapies
Vaccine Therapy
• CDX-110-EGFRvIII
• ICT 107 +/- RT + TMZ: DC vaccine targeting AIM-2, MAGE-1,
TRP-2, gp100, HER-2, IL-13Ra2.
• DC Vax:
• STML-701: Safety and Efficacy Study of SL-701, a GliomaAssociated Antigen Vaccine To Treat Recurrent GBM
– Targets IL-13Rα2 variant, EphA2, and survivin
• CMV vaccine
• HSPPC-96
Viral Therapies
 Toca 511 is murine leukemia virus (MLV)-based replication
competent retrovirus (RCR) that expresses a yeast-derived cytosine
deaminase (CD) gene. This gene is capable of converting the
prodrug 5-fluorocytosine (5-FC) to the antineoplastic drug 5fluorouracil (5-FU).
 The virus stably integrates itself into the genome of the cancer
cell and is therefore available for long-term tumor control.
 DNA-Trix: A Phase II, Multi-center, Open Label study of a
conditionally replicative Adenovirus DNX-2401 for rGBM or GS.
 Targets RB deficient pathway cells and certain cells that contain
certain binding RGD integrins
 A Study of Ad-RTS-hIL-12 (Adenoviral vector) With Veledimex
(activator ligand (INXN-1001) in Subjects With Glioblastoma or
Malignant Glioma
 Creates IL12
Checkpoint Inhibitors
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CTLA-4 I
PD-1
PD-L1
OXO 40