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CHEMOTHERAPY IN GLIOMAS
Dr Boaz VincentPG RegistrarDept of Radiation OncologyChristian Medical College, Vellore
Gliomas
Glioblastoma
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
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
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.
ResultsInitial 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%)
Overall Survival 5-year
OS 9.8 vs. 1.9%.
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.
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
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
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.
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
RTOG 0825
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 B)
10.7 vs. 7.3 months
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
Targeted therapy Anti-angiogenesis drugs - Bevacizumab, Cediranib, Enzastaurin TKI’s - Geftinib, Nimotuzumab, Cetuximab,
Lapatinib mTOR Inhibitors - Everolimus, Tacrolimus Peptide Vaccines - Rindopepimut (CDX-110), PEPvIII
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.
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
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 .
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)
Anaplastic Glioma WHO grade III gliomasConstitute approximately 25% of high-
grade.
RTOG 9402
Arm 1 : PCV followed
by immediate involved-field RT
Arm 2 : RT alone 59.4 Gy in 33 fractions
DOSE DENSE PCV4 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)
PCV plus RT did not prolong the median survival time. 4.6 years- PCV plus RT 4.7 years after RT
1p 19q Codeleted
PCV + RT arm RT alone arm
JCO, 2006
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 cellularity2. Mitosis3. Nuclear abnormalities4. Endothelial proliferation5. Necrosis
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
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
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
CATNON trial
Concurrent and Adjuvant Temozolomide Chemotherapy in NON-1p/19q deleted Anaplastic Glioma
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
CODEL trial
For 1p 19q co deleted patients
Low grade Gliomas
•WHO Grade 1 and Grade 2 •Surgery is the main stay of treatment.
Phase III Study Of Radiation With Or Without PCV Chemotherapy In Unfavorable Low-grade Glioma
INT/RTOG 9802 trial
WHO Gr 2 LGG with Age 18 to 39
years with subtotal resection/biopsy
Age 40 years with any extent resection
HIGH RISK
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.
Updated results 2012
Median OS = 7.5 yrs Vs not reached 5 year OS = 63 % Vs 72%
PFS Median PFS = 4.4 yrs Vs not reached5 year PFS = 46 % Vs 63%
RTOG 0424
129 WHO Grade 2 patients. High risk . Treated with RT / Concurrent and adjuvant TMZ Compared with historical controls received
only RT.
Eligibility WHO grade II astrocytoma,
oligodendroglioma(O), or oligoastrocytoma (OA)
With at least 3 of the following factors: 1. Age 40 years2. Preoperative tumor diameter of 6 cm, 3. Bihemispherical tumor, 4. Astrocytoma histology,5. Preoperative neurological function –
moderate to severe impairment
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.
Pignatti criteria for HR LGG Presence of 3 or more of 1. Age > or = 40 years2. astrocytoma histology subtype3. largest diameter of the tumor > or = 6
cm, 4. Tumor crossing the midline,5. Presence of neurologic deficit before
surgeryPignatti 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.
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
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)
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
Thank You !!
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