This document discusses chemotherapy for gliomas. It begins by covering early trials of carmustine for glioblastoma in the 1960s. It then summarizes the landmark 2005 Stupp trial which showed improved survival with temozolomide combined with radiation therapy for newly diagnosed glioblastoma. The document also discusses trials of bevacizumab and other targeted therapies as well as immunotherapy approaches. It reviews treatment options for recurrent glioblastoma and anaplastic glioma. Finally, it briefly discusses chemotherapy approaches and trials for low-grade gliomas in both adults and children.

1. CHEMOTHERAPY IN
GLIOMAS
Dr Boaz Vincent
PG Registrar
Dept of Radiation Oncology
Christian Medical College, Vellore

2. Gliomas

3. Glioblastoma

4. CHEMOTHERAPY
 BCNU (CARMUSTINE)
 1960s when the Brain Tumor Study Group conducted a
controlled study using BCNU.
 After surgery, patients were assigned to one of four treatment
groups:
 (a) No further therapy,
 (b) BCNU alone,
 (c) Radiation therapy
 (d) Radiation therapy followed by BCNU.
 At 18 months 23% of patients who received radiation therapy
plus carmustine were still alive as compared to 5% with
carmustine or radiotherapy alone

6. Stupp Et al Trial
 Phase III clinical trial conducted by the EORTC
and the National Cancer Institute of Canada
(NCIC).
 This phase III trial randomized 573 patients
with newly diagnosed glioblastoma
 -Between the ages of 18 and 70 years
 -KPS > 70

7. Focal RT daily—30 x 200 cGy;
Total dose: 60 Gy
TMZ 75 mg/m2 PO QD for 6 weeks,
then 150-200 mg/m2 PO QD on Days 1-5 every 28 days for 6 cycles
Concomitant
TMZ + RT* Adjuvant TMZ
Wks6 10 14 18 22 26 30
RT Alone
R
0
*PCP prophylaxis was required for patients receiving TMZ during the concomitant phase.
Stupp R, et al. N Engl J Med. 2005;352:987-996.

9. Results
Initial results: 2005
 Median follow-up28
mont
 TMZ significantly
improved MS (14.6 vs.
12.1 month) P<0.001 by
the log-rank test)
 2-year survival rates of
26% and 6%
 Toxicity:7% grade ¾
hematologic toxicities in
combined arm vs. None
Updated results:2009
 median follow-up of 61
months (range 11 days
to 79 months).
 278 /286 (97%) pts. in
RT alone & 254/287
(89%) in combined-
group died during 5
years of follow-up
 5-year OS (9.8 vs. 1.9%)

10. Overall Survival
 5-year OS
9.8 vs.
1.9%.

11. MGMT
 MGMT is a highly
conserved protein
involved in DNA
repair.
 The enzyme
protects cells
against DNA
damage by
reversing alkylation
at the O6 position of
guanine.

12.  Temozolomide is an alkylating agent that targets
N7 or O6 positions of guanine residues of DNA,
resulting in interruption of cell division and
subsequent cell death.
 MGMT repair DNA damage by demethylating the
O6 position of guanine.
 This returns guanine to its baseline state and
allows cell division to continue.
 When the MGMT promoter is methylated, there is
decreased MGMT transcription

16. Dose dense TMZ in adjuvant
setting
 dd TMZ (75-100
mg/m2 x 21 d) q 4
wks for 6-12 cycles.
 No statistical
difference was
observed between
Arms 1 and 2 for
median OS (16.6,
14.9 mo, p = 0.63),
or median PFS (5.5,
6.7 mo, p = 0.06), or
by methylation
status

17. Bevacizumab in Newly diagnosed
GBM
 GBM is a highly vascular tumor.
 BVZ is a therapeutic antibody that specifically
binds to the VEGF protein theoretically
interfering blood supply of tumour, hence
stopping the growth of cancer cells.
 Based on Ph 2 studies BVZ is approved in 60
countries for the treatment of recurrent high
grade gliomas.

18.  Arm A: Concomitant
RT, TMZ and
BVZ (10g/kg)
 Adjuvant BVZ and
TMZ for 6 cycles
followed by BVZ
monotherapy (15
mg/kg) every 3 weeks
until progression.
 PFS : 10.6 months
 OS : 16.8 months
 Arm B: Concomitant
RT, TMZ, and placebo
 Adjuvant placebo and
TMZ for 6 cycles
followed by placebo
monotherapy every 3
weeks until
progression.
 PFS : 6.2 months
 OS : 16.7 months
AVAGlio Trial
Added to standard of care

19. RTOG 0825

20.  The median rates of
overall survival were
similar in the
bevacizumab and
placebo groups
(Panel A).
 15.7 and 16.1
months.
 The median rate of
progression-free
survival was higher
in the bevacizumab
group but did not
reach the
prespecified
threshold for
significance (Panel

21. GLARIUS Trial
 Arm A:
 Concomitant RT,
BVZ, and Irinotecan.
Adjuvant BVZ and
Irinotecan until
progression
 PFS : 9.7 mo
 OS : 16.6 mo
 Arm B:
 Standard treatment:
concomitant RT and
TMZ + adjuvant
TMZ for 6 months.
 PFS : 6.0 mo
 OS : 17.3 mo
Compared with standard of care

22. Targeted therapy
 Anti-angiogenesis drugs
- Bevacizumab, Cediranib, Enzastaurin
 TKI’s
- Geftinib, Nimotuzumab, Cetuximab,
Lapatinib
 mTOR Inhibitors
- Everolimus, Tacrolimus
 Peptide Vaccines
- Rindopepimut (CDX-110), PEPvIII

23. Immunotherapy - Therapeutic
Vaccines
 RINDOPEPIMUT- therapeutic vaccine. The
central component of rindopepimut is a fragmentof
a mutated form of the epidermal growth factor
receptor (EGFR) protein called EGFRvIII.
 Approx 20 to 30 % of GBM express EGFRvIII.
 Improvement in both median OS and 6-month
PFS in patients received the vaccine
and Bevacizumab compared with patients who
received a placebo vaccine.

24. Treatment at Recurrence
 Currently, AVASTIN is approved in 60 countries
worldwide for treatment of progressive GBM
following prior therapy.
 Kreisl et al.
 Study of 49 glioblastoma patients, reported
 objective response rate of 35%,
 6-month progression-free survival of 29%,
 3.7-month median progression-free survival,
 7.2-month median overall survival

25. OPTIONS
 TMZ RECHALLENGE.
 RESCUE study : 50 mg/m2/day for up to 1
yr.
 DOSE INTENSE TMZ
• 150 mg/m2/day one week on, one week
off
• 100 mg/m2/day 3 weeks on, one week off
 NITROSOUREAS : PCV / Carmustine .

26. Gliadel Wafers
 Polymer-based local chemotherapy
(carmustine wafers) implanted in
surgical cavity intraoperatively.
 Randomized trial that included 222
patientswith recurrent glioma (mostly
GBM)
 Survival increased from 44% to 64%
at 6 months (p = .02).
 Median survival increased from 23 to
31 weeks.
 (Brem et al , Lancet 1995)

27. Anaplastic Glioma
 WHO grade III gliomas
Constitute approximately 25% of high-grade.

28. RTOG 9402
 Arm 1 :
 PCV followed
by immediate
involved-field
RT
 Arm 2 : RT
alone 59.4 Gy
in 33 fractions
DOSE DENSE PCV
4 cycles were given every 6
weeks before RT
• Lomustine 130 mg/m2 orally
on day 1
• Procarbazine 75 mg/m2 orally
OD, days 8 -21
•Vincristine 1.4 mg/m2 on days
8 and 29 ( No max dose 2mg)

29.  PCV plus RT did not prolong the median survival time.
 4.6 years- PCV plus RT
 4.7 years after RT

30. 1p 19q Codeleted
 PCV + RT arm RT alone arm

31.  JCO,
2006

32.  Whether adjuvant
PCV at the time of
diagnosis as opposed
to chemo at
recurrence would
improve overall
outcome ??
 368 patients between
August 13, 1996 and
March 3, 2002
STUDY ELIGIBILITY
 At least three of five
anaplastic
characteristics present .
1. High cellularity
2. Mitosis
3. Nuclear abnormalities
4. Endothelial
proliferation
5. Necrosis

33.  Lomustine 110 mg/m2
orally on day 1
 Procarbazine 60 mg/m2
orally on days 8 to 21
 Vincristine 1.4mg/m2 IV
on days 8 and 29 (with
a maximum dose of 2
mg).
 Cycles were to be
repeated every 6 weeks
 Radiotherapy : 59.4
Gy in fractions of 1.8
Gy.
 PCV chemotherapy
consisted of six
cycles of standard
PCV chemotherapy
given in 6 week, and
was started within 4
weeks after the end of
RT.
STANDARD PCVTREATMENT

34. A. OS, B. PFS
 OS and PFS
significantly better
in the RT/PCV arm
.
 Median OS:
42.3 v 30.6 months
 Median PFS :
24.3 v 13.2
months

35. Subgroup Analysis by 1p/19q
Status
 CO- DELETED
RT/PCV Vs RT
 OS : Not Reached
Vs 112 months
 PFS : 157 Vs 50
months
 NON CO-DELETED
RT/PCV Vs RT
 OS : 25 Vs 21 months
 PFS : 15 Vs 9 months
In 80 of the 316 cases (25%) codeletion of 1p/19q was
found

36. CATNON trial
Concurrent and Adjuvant Temozolomide
Chemotherapy in NON-1p/19q deleted Anaplastic
Glioma

37.  2016 ASCO update
 5-year survival rates of 56% when
temozolomide was added to RT compared
with survival rates of 44% in patients who did
not receive the adjuvant chemotherapeutic
agent.
 ‘‘Temozolomide given after RT improves
survival in this disease. But we need to follow
up to further elucidate the role of concurrent
temozolomide.”
 Final results by 2020

38. CODEL trial
For 1p 19q co deleted patients

39. Low grade Gliomas
•WHO Grade 1 and Grade 2
•Surgery is the main stay of treatment.

40. Phase III Study Of Radiation With Or Without PCV
Chemotherapy In Unfavorable Low-grade Glioma
INT/RTOG 9802 trial

41. WHO Gr 2 LGG
with
 Age 18 to 39
years with
subtotal
resection/biopsy
 Age 40 years
with any extent
resection
HIGH RISK

42. INT/RTOG 9802 trial
 From 1998 to 2002,
 251 patients .
 Initial Results in 2006
 6 year follow up.
 Trend toward improved 5 year PFS 63 vs.
46%(p = 0.06)
 Acute grade 3/4 toxicity occurred in 67% in RT
plus PCV, vs. 9% in RT alone.

43.  Updated results 2012
 Median OS = 7.5 yrs Vs not reached
 5 year OS = 63 % Vs 72%

44. PFS
Median PFS = 4.4 yrs Vs not reached
5 year PFS = 46 % Vs 63%

45. RTOG 0424
 129 WHO Grade 2 patients.
 High risk .
 Treated with RT / Concurrent and adjuvant
TMZ
 Compared with historical controls received
only RT.

46. Eligibility
 WHO grade II astrocytoma,
oligodendroglioma(O), or oligoastrocytoma
(OA)
 With at least 3 of the following factors:
1. Age 40 years
2. Preoperative tumor diameter of 6 cm,
3. Bihemispherical tumor,
4. Astrocytoma histology,
5. Preoperative neurological function –
moderate to severe impairment

47.  The 3-year OS rate is 73.1% , Significantly
higher than the historical control OS rate of
54%.
 3-year PFS was 59.2% and median PFS - 4.5
years
 COX analysis showed :
 Only histology was significantly associated
with OS and PFS .
 The other factors were not significantly
associated with either OS or PFS.

48. Pignatti criteria for HR LGG
 Presence of 3 or more of
1. Age > or = 40 years
2. astrocytoma histology subtype
3. largest diameter of the tumor > or = 6 cm,
4. Tumor crossing the midline,
5. Presence of neurologic deficit before surgery
Pignatti F, van den Bent M, Curran D, et al. Prognostic
factors for survival in adult patients with cerebral low-
grade glioma. J Clin Onco 2002;20:2076-2084.

49. Pediatric Gliomas
 To defer radiotherapy and its adverse effects,
chemotherapy is now the front-line adjuvant
therapy for children with progressive low-grade
gliomas.
 The combination of carboplatin and vincristine
has shown to result in tumor reduction and a
3-year PFS of 68%.
 Alternative :
 Children's Oncology Group protocol – TPCV
Thioguanine/procarbazine/CCNU/vincristine

50. Pediatric LGG
 Carboplatin and vincristine chemotherapy for
children with newly diagnosed progressive low-
grade gliomas.
 78 children
 Mean age :3 years (3 months—16 years)
 PFS : 75% at 2 years and 68% at 3 years
 Treatment with carboplatin and vincristine is
effective, especially in younger children, in
controlling newly diagnosed progressive low-
grade gliomas.
 (Journal of Neurosurgery May 1997 / Vol. 86 / No. 5)

51. QOL in survivors
 TMZ – a radiosensitiser . Can increase the
neurotoxicty of radiation also !!
 Cognitive decline – 50%
 40-60% patients resume their same work.
 Mood disturbences
 Sleeplessness
 Fatigue

52. Thank You !!