Brain tumors Dr Belal ElhawwariC Radiation Oncologist

The Hashemite Kingdom of Jordan

Population 6,508,271 (July 2011 est.)

Age structure 0-14 years: 35.3% (male 1,180,595/female 1,114,533)

15-64 years:

59.9% (male 1,977,075/female 1,921,504)

65 years and over : 4.8% (male 153,918/female 160,646) (2011 est.)

Trend of cancer in Jordan, 1980-2009

Ten most common cancers among Jordanian Males, 2009

Rank Cancer No %

1 Colorectal 290 12.7

2 Lung 256 11.2

3 Leukemia 189 8.3

4 U.Bladder 184 8.1

5 Prostate 179 7.9

6 Non- Hodgkin's Lymphoma 128 5.6

7 Brain & CNS 100 4.4

8 Larynx 88 3.9

9 Stomach 68 3.0

10 Hodgkin's Disease 68 3.0

Ten most common cancers among Jordanian Females , 2009

Rank Cancer No %

1 Breast 926 36.8

2 Colorectal 264 10.5

3 Thyroid 140 5.6

4 Leukemia 114 4.5

5Non- Hodgkin's Lymphoma 110 4.4

6Corpus Uteri & Unspecified 104 4.1

7 Hodgkin's Disease 79 3.1

8 Stomach 77 3.1

9 Ovary 75 3.0

10 Brain &CNS 72 2.9

Trend of cancer in Jordan, 1980-2010

Ten most common cancers among Jordanian Males, 2010

Rank Cancer No %

1 Colorectal 332 14.2

2 Lung 311 13.3

3 Prostate 218 9.4

4 U.Bladder 186 8

5 Leukemia 127 5.5

6 Non- Hodgkin's Lymphoma 120 5.2

7 Brain & CNS 106 4.5

8Stomach

90 3.9

9 Larynx 74 3.2

10 Hodgkin's Disease 65 2,8

Ten most common cancers among Jordanian Females , 2010

Rank Cancer No %

1 Breast 941 37.4

2 Colorectal 226 9.0

3 Thyroid 136 5.4

4Non-Hodgkin lymphoma 130 5.2

5 Uterus 113 4.5

6 Leukemia 91 3.6

7 Ovary 84 3.3

8 Lung 68 2.7

9 Hodgkin disease 67 2.7

10 Stomach 62 2.5

Top ten cancers among Jordanian both sexes, 2010

Age-Standardized Incidence Rate per (100,000 )population for Male cancers ( all sites) , Jordan compared with other countries .

Radiotherapy plus Concomitant & Radiotherapy plus Concomitant & Adjuvant Temozolomide for Adjuvant Temozolomide for

GlioblastomaGlioblastoma

Roger Stupp, M.D., Warren P. Mason, M.D., et al,

European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups and the National Cancer Institute of Canada Clinical Trials Group

Volume 352 Issue 10 , 10 March 2005, Pages 987-996

Surgical resection ,safely feasible

Adjuvant Radiotherapy

adjuvant carmustine,(a nitrosourea drug )used in the USA .

Treatment of Glioblastoma

No survival benefit Compared with RTX

alone

randomized phase 3 trial of nitrosourea -based adjuvant chemotherapy Stupp R, et al . ASCO 2003 , American Society of Clinical Oncology, 2003:779-88.

Introduction

Temozolomide as a single agent

reduces the DNA-repair enzyme (MGMT) in

tumor tissue

Treatment of recurrent gliomas

longer survival especially patients with glioblastoma

Hegi ME, et al.. Clin Cancer Res 2004;10:1871-1874

Introduction

Antitumor activity

Concomitant:temozolomide

+ fractionated radiotherapy

adjuvant Temozolomide

6 cycles

two-year survival rate, 31 %

pilot phase 2 trial in patients Glioblastoma

promising clinical activity

Stupp R et al.. J Clin Oncol 2002;20:1375-1382

Introduction

Concomitant:temozolomide

+ fractionated radiotherapy

Radiotherapy alone

phase 3 trial in patients Glioblastoma

Comparing

therefore the (EORTC) & the (NCIC) initiated this trial

adjuvant Temozolomide

6 cycles

the (EORTC) & the (NCIC) trial patients

Eligibility criteria :*newly diagnosed glioblastoma (grade IV astrocytoma)*p/s 2 or less *adequate renal ,Hematologic & hepatic function

baseline examination:1. CT-scan or MRI 2. CBC & chemistry 3. physical examination 4. pathology review

573 patients from 85 institutions in 15 Countries

The median age : 56 years

84% underwentdebulking surgery

Histologic slides were submitted for 85%

pathological review confirmed in 93 %

the (EORTC) & the (NCIC) trial Methodology & Design

573 patients from 85 institutions in 15CountriesFrom August 2000 until March 2002

End point :Overall survival

Randomlyassigned toreceive

Radiotherapy+temozolomide(287 patients)

Radiotherapy(286 patients)

the (EORTC) & the (NCIC) trial treatment - Radiotherapy alone

14 75

21 35 28

week 1

week 2

week 3

week 4

week 5

week 6

Radiotherapy 60 Gy/ 30 fractions /6 weeks

day 1 43

GTV (tumor without edema )CTV (GTV+ 2-3 cm margins)Planned with CT-scan + 3D planning system Radiotherapy deliveredwith 6MV linear & more

the (EORTC) & the (NCIC) trial treatment - RTx+Temodal

14 75

21 35 28

week 1

week 2

week 3

week 4

week 5

week 6

Radiotherapy 60 Gy/ 30 fractions /6 weeks

day 1 43

GTV (tumor + edema )CTV (GTV+ 2-3 cm margins)Planned with CT-scan + 3D planning system Radiotherapy deliveredwith 6MV linear & more

the (EORTC) & the (NCIC) trial treatment - RTx+Temodal

Radiotherapy 60 Gy/ 30 fractions /6 weeks

day 1 14 75

21 35 28 43

week 1

week 2

week 3

week 4

week 5

week 6Temodal75 mg/m2

Daily 7 DTemodal75 mg/m2

Daily 7 D

Temodal75 mg/m2

Daily 7 D Temodal75 mg/m2

Daily 7 D

Temodal75 mg/m2

Daily 7 D

Temodal75 mg/m2

Daily 7 D

4 week

BreakAdjuvantTemodal

Temodal 5 days every 28days for 6 cycles

150 mg/m2 cycle 1200 mg/m2 cycle 2200 mg/m2 cycle 3200 mg/m2 cycle 4200 mg/m2 cycle 5200 mg/m2 cycle 6

GTV (tumor without edema )CTV (GTV+ 2-3 cm margins)Planned with CT-scan + 3D planning system Radiotherapy deliveredwith 6MV linear & more

the (EORTC) & the (NCIC) trial Results

At a median follow up 28 months480 pts (84%) died Median survival:RTx alone :12.1 months RTx+Temadal :14.6 months

The 2 yrs survival :RTx alone :10.4% RTx+Temadal :26.5%

the (EORTC) & the (NCIC) trial Results

The median progression-free survival was:RTx alone : 5.0 monthsRTx+Temadal : 6.9 months

The progression-free survival at 12 months :

RTx alone :9.1% RTx+Temadal :26.9%

adverse events

No grade 3 or 4 hematologic toxic effects were observed in the radiotherapy group

During concomitant temozolomide therapy

During adjuvant temozolomide therapy

The effects of TEMODAL and MGMT on methylation status of DNA. Adapted from MGMT and Objection Handling.ppt

TEMODAL is an alkylating agent that kills cells by adding a methyl group to DNA. DNA damage caused by TEMODAL culminates in cell death through apoptosis. One enzyme that is known to repair the DNA damage caused by alkylating agents such as TEMODAL is O6-methylguanine-DNA methyltransferase (MGMT

MGMT is expressed in all cells. MGMT repairs damaged DNA by removing methyl groups from the O6 position of DNA guanines. Once MGMT has removed one methyl group, it is inactivated. It would seem reasonable therefore that lower MGMT levels in tumour cells might result in a higher response following TEMODAL administration, and conversely high MGMT levels might translate into a lower response rate.

the (EORTC) & the (NCIC) trial treatment - Conclusion

the addition of temozolomide to radiotherapy provides

a statistically significant survival benefit with minimal toxicity

the regimen of radiotherapy plus temozolomide should serve as :

the new platform from which we need to explore for new regimens for treating malignant gliomas.

Thank you

ASCO 2013 data

A phase II trial of lithium, bevacizumab, temozolomide, and radiation for newly diagnosed glioblastomas (GBM)

. This phase II study evaluated the safety and efficacy of using lithium and bevacizumab (BEV) in newly diagnosed GBM.

Conclusions: The strategy of targeting angiogenesis and invasion simultaneously in newly diagnosed GBM is effective and feasible. Clinical trial information: NCT01105702.

Final results of a single-arm phase II study of bevacizumab and temozolomide following radiochemotherapy in newly dignosed adult glioblastoma patients

This study evaluated efficacy and safety of bevacizumab (BEV) added to the post-radiation treatment phase for patients with newly diagnosed glioblastoma (GBM).

Participants received standard radiation therapy (RT) within 6 weeks of surgery, and concomitant administration of temozolomide (TMZ)

Four weeks after radiation, treatment with TMZ (Days 1-5 of a 28 day cycle) with BEV, (days 1 and 15 of a 28 day cycle) was started, and continued until disease progressed or adverse effects indicated need to stop treatment.

). Results suggest that the addition of bevacizumab to the post-RT phase of treatment improves both PFS and OS for persons with GBM despite the high percentage of participants being unable to progress to post-radiation treatment. Clinical trial information: NCT005906

 Temozolomide plus bevacizumab in elderly patients with newly diagnosed glioblastoma and poor performance status: An Anocef phase II trial

evaluated the efficacy and safety of the combination of TMZ with bevacizumab (BV) as an initial treatment for elderly patients with GBM and KPS<70.

Conclusions: This study confirms that TMZ-based treatment is of help in elderly GBM patients with poor KPS. However, the addition of bevacizumab does not appear to be of benefit in term of PFS and OS.

Survival benefit from bevacizumab in newly diagnosed glioblastoma (GBM) according to transcriptional subclasses.

Background: Genome-wide transcriptional studies (TCGA and others) have identified distinct GBM molecular subtypes, but to date this has not translated into prognostic or therapeutic implications. Bevacizumab has emerged as a new treatment option for GBMs, although a survival benefit has yet to be demonstrated in unselected patients (pts).

We analyzed outcomes from a prospective phase II trial in newly diagnosed GBM treated with hypofractionated stereotactic radiotherapy (HFSRT) combined with temozolomide and bevacizumab, and correlated with GBM transcriptional subclasses.

Conclusions: We provide proof-of-principle that GBM transcriptional classification is biologically and therapeutically relevant, identifying non pro-neural GBMs as the best candidates for bevacizumab treatment.

Our findings imply that angiogenesis and tumor invasion mechanisms in proneural tumors may be distinct from other subtypes, and we suggest such pts should not be offered bevacizumab treatment upfront. Future randomized trials focusing on non-proneural tumors may finally demonstrate a survival advantage for bevacizumab in GBM. Clinical trial information: NCT01392209.

Progression-free survival (PFS) and health-related quality of life (HRQoL) in AVAglio, a phase III study of bevacizumab (Bv), temozolomide (T), and radiotherapy (RT) in newly diagnosed glioblastoma (GBM).

: GBM has a high disease burden and poor prognosis, and impacts negatively on HRQoL. Symptomatic therapies for GBM, such as corticosteroids (CS), may impact patient status negatively Methods: AVAglio, a randomized, double-blind, placebo (P)-controlled trial in patients (pts) ≥18 yrs with newly diagnosed GBM, evaluated the addition of Bv or P

Bevacizumab in combination with TMZ in patients with recurrent GBM: Final OS and PFS analysis

BEV provides a consistent clinical benefit in the treatment of relapsing GBM in terms of a delayed progression and increased median overall survival compared to historical controls. The aim of this study is to evaluate the efficacy and toxicity profile of the combination of BEV with dose dense TMZ, reporting the final results of PFS, OS and the toxicity experienced

Conclusion: Although the combination don’t met the previous reported activity of BEV, 19% of patients had longer survivals which suggest the need to identify patients that benefit for this treatment. Clinical trial information: NCT01115491

Tumor response based on adapted Macdonald criteria and assessment of pseudoprogression (PsPD) in the phase III AVAglio trial of bevacizumab (Bv) plus temozolomide (T) plus radiotherapy (RT) in newly diagnosed glioblastoma (GBM).

Conclusion: Addition of Bv to 1st-line T/RT significantly improves ORR. The rate of confirmed PsPD was low in both arms. Clinical trial information: NCT00943826

Conclusion

Thank you