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 !!