Role

of Chemotherapy in Glioma
with Temozolomide

Djohan Ardiansyah
Neurooncology Division, Universitas Airlangga/ Dr.
Soetomo General Hospital
Surabaya
 Outline
Presentation 01
Glioma and its nature

Chemotherapy in glioma
02

Action of Temozolomide in
03 glioma

Why can glioma recur after

04 temozolomide? Will
Temozolomide still use?

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 Glioma
- The most commond primary intracranial
tumour : 81% of malignant brain tumour

- Incidence rate 4,67-5,73 /100000person,

glioblastoma: 0,59-3.69/100000person

- Survival after diagnosis: age, KPS, extend

of resection, histology type, molecular
genetic

- New WHO classification based on

molecular pathology and genetic
predispotition. Those contribute to
prognose and risk: 1p19q codeletion, IDH
mutation, TP53 mutation, ATRX loss, etc

Queen TO,et al. Neuro-Oncology 16(7), 896–913, 2014

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 2007 WHO Classification of Glioma 2016

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 Survival Expectancy:
The Importance of Histologic Grading

Tumor Type Median Survival (years)

Low-grade oligodendroglioma 4-101

Low-grade astrocytoma 51
Anaplastic oligodendroglioma 3-41
Anaplastic astrocytoma 31
Glioblastoma multiforme <11

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1DeAngelisLM. Brain tumors. N Engl J Med. 2001;344:114-123.
 Glioma growth and invasiveness

LOH in downregulation Amplification

1p19q PTEN of PDGFRα

Genetic Oligodendroglioma
alteration
Amplification Loss of Amplification of PDGFRα, β yg
4q12 p53 mengkode ligand PDGF A,B,C,D
1
Astrositoma Mutasi gene Deletion Mutation
Loss of 22q
p16INK4A 13q13 p53
Mutation Deletion PTEN- LOH of
Loss of 9p
chr7 >é AKT/mTOR 10q

“Grow”: proliferating
2 “CSC”à CD133
3
GFR : EGFR+PDGFR+cMet
CAR : integrins, ephrins, CD44
Protease : serine, cathepsin,MMPs
ADAMTS “Go”: migrating

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Akira Hara, et al. Journal of Oncology (2019);2019:2964783
 TARGETTED
IMUNOTHERAPY
THERAPY
PROTON
RADIATION DYNAMIC
THERAPY

ALTERNATING
CHEMOTHERAPY ELECTRIC FIELD
THERAPY

SUPPORTIVE
SURGERY GLIOMA CARE /
PALIATIVE
THERAPY

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 Surgery
• Extent of surgery
à strong predictor of outcome
à biopsy, subtotal resection (STR), gross total resection (GTR)
à retrospective metaanalisis in 4100 pts GBM who undergo
GTR vs STRà increase survival in one year 61%vs 51%

Montserrat LV, et al (2017). Brain Sciences 7;166:1-16

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 INTRAOPERATIVE MRI IONM

ADVANCED
SURGERY

FUNCTIONAL BRAIN
5 ALA FLUORESCENT
MAPPING

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 02 Chemotherapy in glioma

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 Chemotherapy overview

• Become common adjunctive treatment of malignant brain

tumors or selected benign neoplasma patients nowadays
• Give one/more agent in order to kill or control biological
behaviour of tumor cell
• Challenge:
à effective dose to expose to brain tumors (blood brain-
blood tumor barrier )
à drugs with non-ionized, small lipid soluble molecules
à regional blood flow and tumor capillary permeability

Newton HB, Handbook of Brain Tumor Chemotherapy, Chap 2, 21-38

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 Type of Chemotherapy in glioma
Cell-cycle specific agents
• Attack tumor during certain phases of cell cycle (S-phase, mitosis) à
vincristine, etoposide
Cell-cycle non specific agents
• Attack tumor during all the phases of cell cycle and not limited by the size
of growth fractionà Temozolomide, BCNU, cisplatin

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 Chemotherapy in low grade glioma

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 Objective : to know effect of before, during, after temozolomide in natural progression of
LGG ( mean tumor diameter (NTD))

Distribution of 1p19q codetion/not Distribution of overexpression

pts before TMZ: 3,4mm vs p53/not pts before TMZ 6,3mm vs
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5,9mm/year
DJO 4,2 mm/year 15
 During TMZ there was decreasing 9,2mm/years of MTD in 1p19q codeletion
(n=30)/not (n=38) pts , and increasing of MTD after discontinued TMZ

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Objective: association of extent of surgery, radiation, Chemotherapy and mortality, PFS at
2, 5, 10 years. (PCV, nitrosourea )

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Timothy JB, et al, (2019). Neuroncology practice 64(8): 249-58
 Adverse event:
- Bone morrow toxicity, diarrhea,
fatique, and hepatotoxicity
- Grade 3and 4 hematological/bone
marrow toxicity 9,1%-41,6% and
9,6%ofpts

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 Adverse event:
- Haematological
/Bone marrow
toxicity 7% grade 3,
8% grade 4
- Gastrointestinal
problems

CONCLUSION:
à Adjuvant PCV: Increase PFS and OS In high risk LGG, 1p19q codeletion LGG, IDH mutant
à RT/TMZ + Adjuvant TMZ: LGG with unfavourable history (IDH wild type, 1p19q intact)
à Therapy with TMZ shows lesser toxicity than PCV

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 Chemotherapy in anaplastic glioma dan glioblastoma

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 TMZ in AA: Study Schematic
• Histologically confirmed AA
No prior
• Failed radiotherapy ± chemotherapy
chemotherapy with 200 mg/m2 qd x 5 d
nitrosourea
• KPS ≥ 70 6-mo
• No previous stereotactic or PFS
interstitial radiotherapy
Prior
chemotherapy
KPS = Karnofsky performance 150 mg/m2 qd x 5 d
Status
PFS = Progression-Free Survival
AA = Anaplastic Astrocytoma

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1. Yung WKA et al. J Clin Oncol. 1999; 17:2762 – 2771
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 1.0

0.8
Survival rates

Median = 13.6 months

0.6

0.4 Overall survival

6-mo PFS = 46%
0.2

Progression-free survival (PFS)

0.0
0 3 6 9 12 15 18 21 24
Time (months) from start of
treatment

* Intent-to-treat population, includes

anaplastic astrocytoma and
anaplastic oligoastrocytoma.
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Yung WKA et al. J Clin Oncol. 1999;17:2762-2771.
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Objective: to evaluate HR-QOL recurrent AA pts treated by TMZ with EORTC QLQ-C30 &BCM20

Conclusion: recurrent AA pts have improvement of social function and global QOL with TMZ
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 Key trial of adjuvant PCV to radiotherapy in anaplastic glioma

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Ammirati M,et al (2017).JNCCN 15:11
Key trial adjuvant TMZ to RT in anaplastic glioma

!!!!

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Ammirati M,et al (2017).JNCCN 15:11
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NCCN Guideline for CNS v2 2020
EORTC 22981/NCIC treatment scheme and overall survival diagram

-Median survival:
22 vs 13 months
-2years survival:
46% vs 14%

Stupp, et all (2005). NEJM 352:987-996,

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Hegi ME, et all (2005). NEJM 352:997-1003
 Adverse Events
Concomitant Phase
Maintenance Phase
Radiotherapy +
Temozolomide
Temozolomide
(N=224)
(N=288)
Adverse Event Number (%) of Patients
All Grade >3 All Grade >3
Alopecia 199 (69) 0 124 (55) 0
Fatigue 156 (54) 19 (7) 137 (61) 20 (9)
Nausea 105 (36) 2 (1) 110 (49) 3 (1)
Vomiting 57 (20) 1 (<1) 66 (29) 4 (2)
Anorexia 56 (19) 2 (1) Grade 33 (1)
61 (27) or 4 Hematologic Toxic Effects
Headache 56 (19) 5 (2) 51 (23) 9 (4) Concomita
nt TMZ Adjuvant TMZ Entire Study
Constipation 53 (18) 3 (1) 49Toxic
(22) Effect 0 Therapy Therapy Perioda
(N=284), n (N=223), n (%) (N=284), n (%)
Convulsions 17 (6) 10 (3) 25 (11) 7 (3) (%)
Thrombocytop
11 (4) 8 (3) Leukopenia
19 (8) 8 (4) 7 (2) 11 (5) 20 (7)
enia
Neutropenia 12 (4) 9 (4) 21 (7)
Thrombocytopeni
9 (3) 24 (11) 33 (12)
a
Anemia 1 (<1) 2 (1) 4 (1)
Any 19 (7) 32 (14) 46 (16)
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1. Stupp R et al. N Engl J Med. 2005; 352:987–996
 Result
Died 532(93%) of Median follow
573 up 61 month

HR for died TMZ+Rad to Rad: 0,63

TMZ+Rad (287) Rad only (286)

Overall 27,2% at 2yrs 10.9% at 2yrs

survival 16% at 3yrs 4,4% at 3yrs
(OS) 12,1% at 4yrs 3% at 4yrs
9,8% at 5 yrs 1,9% at 5 yrs
HR 0,6
PFS 11,2% at 2yrs 1,8% at 2yrs
6% at 3 yrs 1,3% at 3 yrs
5,6% at 4 yrs 1,3% at 4 yrs
4,1% at 5 yrs 1,3% at 5 yrs
HR 0,56
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 Temozolomide for GBM

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NCCN Guideline for CNS v2 2020
 Temozolomide for GBM

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NCCN Guideline for CNS v2 2020
 03 Action of Temozolomide in glioma

Temozolomide
- An imidazote-trazine derivative of dacarbazine
- Alkylating chemotherapy agent, stable in acidic ph<7
- Prodrug, rapid hidrolyse to active MTIC 5-(3methy-1triazeno)
imadazole-4-carbozamide)
- Oral administration with bioavailability 100%. Mean peak
plasma concentration 60min

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(5aminoimidazole 4 carboxamide 3
methyltriazen 1 yl imidazole 4
carboxamide)
7/4/20 DJO (Carboxamide 3 methyl triazene 1yl 39
Olga M, et al.2015 Rsc Adv 5 28219-27 midazole 4 carboxamide)
 Temozolomide action

Tumor cell

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 Temozolomide – Side Effects

• Tiredness / fatigue
• Hair loss
• Loss of appetite
• Nausea, emesis
• Constipation (from anti-emetics)
• Headache
• Low blood counts – red/white/platelets
– Particularly lymphocytes (risk of Pneumocystis carinii
pneumonia)
• Rash
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 Why can glioma recur after temozolomide?
04 Will Temozolomide still use?

- Chemoresistant of alkylating agent mechanism in glioma

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Sarkaria,et al. Clin Cancer Res 14(10): 2900-8
- Heterogenicity and complexity of signal transduction and gene
expression in glioma

TIAF1 and GBM CSCà pPTEN Olig2 and

amyloid fibril expresion CD133 VEGF
and nestin

- Glioma cell with mutation and low expression of DNA-

mismatch repair, high expression of AGT (O6 alkyl guanine
DNA alkyl transferase), and BER

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Treatment option for recurrence:
- Surgery
- Chemotherapy: Temozolomide, lomustine, carmustine, PCV,
cyclophospamide, platinum-based regimens
- Targetted therapy: Bevacizumab, Nimotuzumab
- Alternating field therapy
- Proton Dynamic therapy
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 Alternative dose schedule of temozolomide in rHGG
Result:
> reduce resistance and induce anti angiogenic
- dose dense 7days on/7days off (100-150mg/m2) effect
à PFS 6months 34,8%, PFS 12 months 15,5% (Grade IV)
> sustained depletion of MGMT
à OS rate at 12 months 79% (grade III)
- dose dense 21 days on/7days off (75-100mg/m2)
à OS rate at 6 months 73,6%, 12 months 40,6% (grade IV)
- standart dose (150-200mg/m2) significantly higher clinical benefit, but has greatest
toxicity rate of grade3-4 lymphopenia (76,5%)

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 Conclusion

• Glioma is a primary brain tumor that challenging in treatment

• Chemotherapy with temozolomide is the standart treatment
for glioma in different type and characteristic according to
NCCN 2020
• Temozolomide is an oral alkylating chemotherapy agent which
has lesser side effect and more tolerable than others
• Future trials are needed to overcome recurrent HGG patient

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 Thank you for your attention

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 Progressive Disease

• Challenges of diagnosing progressive disease

– Pseudo-progression
– increase in enhancement without tumor progression
– Especially after chemo-radiation
– First post-RT MR scan should not be used for treatment
decisions
– ‘Treat the patient not the scan’
• Techniques to help distinguish - MRS (spectroscopy), PET
scans, SPECT scans

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 Langkah tatalaksana High Grade Astrocytoma

Evaluasi terapi pada High grade Astrocytoma (GBM)

CR&PR dikonfirmasi ≥4 mgg

terapi concomittan, lesi
menetap atau tidak à
Pseudoresponse vs CR/PR
Evaluasi awal dalam 4 minggu
post radiokemoterapi, 12 mgg
post radiokemoterapi
Pseudoprogression vs PD

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Langkah tatalaksana High Grade Astrocytoma

Keterangan gambar:
a. T1+C setelah reseksi tumor
b. T1+C 4minggu setelah kemoradiasi à area enhance à
pseudoprogression
c. T1+C 12 minggu setelah kemoradiasi à area enhance ↓
d. T1 +C beberapa minggu setelahnya à area enhance ↓↓↓

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 Langkah tatalaksana High Grade Astrocytoma

Keterangan:
Evaluasi pada sekuen T2/flair à lesi nonenhance dengan area hiperinten abnormal
yang mungkin suatu tumor progression
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 Diagnosa GBMb

GBMb
Pseudoprogression

MRI masih menjadi baku emas diagnosa

-MRI+kontras seharusnya dilakukan 24-72 jam setelah operasi

-Evaluasi 2-3 bulan sekali Hou et al 2006

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 GBMb Pseudoprogression

Peningkatan rasio Penurunan rasio

cholin/kreatin,
cholin/NAA (>1,8),
cholin/kreatin,
adanya laktat penurunan NAA

Mean ADC, dan Mean ADC,

rasio ADC signifikan danRasio ADC
lebih rendah signifikan lebih
tinggi

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 GBMb Pseudoprogression

peningkatan penurunan
signifikan relatif signifikan relatif
CBV (>2,6)dan PH, CBV (<0,6)dan PH,
penurunan relatif peningkatan
PSR relatif PSR

Peningkatan Penurunan
metabolik tumor metabolik tumor
FDG, C-MET, F-FET, FDG, C-MET, F-FET,
atau F-FLT atau F-FLT

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 GBMb

Neovaskuler di
sekeliling tumor

Pseudoprogression

Dilatasi vaskuler
Fokal nekrosis

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 Kriteria GBMb
• Kriteria Mc Donald • Kriteria RANO
- Peningkatan > 25% area yg -peningkatan >25% area yang
menyerap kontras /
menyerap kontras yang respon baik
- Adanya lesi baru / pd dosis steroid stabil / meningkat ,
- Perburukan gejala neurologi dan /
-peningkatan area yang tidak
Limitasi: menyerap kontras pada T2/flair
Area yang menyengat kontras pada dosis steroid stabil/meningkat
dapat disebabkan: perubahan - lesi baru
dosis steroid, kejang, post operasi, -perburukan gejala bukan karena
iskemia dan nekrosis post terapi sebab non tumoral
-kegagalan evaluasi akibat
kematian atau kondisi buruk

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