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Brain tumors rt& ctx
 

Brain tumors rt& ctx

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Brain tumors the role of Radiotherapy and chemotherapy

Brain tumors the role of Radiotherapy and chemotherapy

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  • 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 (see Figure 5-4). 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. <br />

Brain tumors rt& ctx Brain tumors rt& ctx Presentation Transcript

  • Brain tumors C Dr Belal Elhawwari 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, 19802009
  • Ten most common cancers among Jordanian Males, 2009 Rank 1 2 3 4 5 6 7 8 9 10 Cancer No % Colorectal 290 12.7 Lung 256 11.2 Leukemia 189 8.3 U.Bladder 184 8.1 Prostate 179 7.9 Non- Hodgkin's Lymphoma 128 5.6 Brain & CNS 100 4.4 Larynx 88 3.9 Stomach 68 3.0 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 4 114 4.5 110 4.4 6 Leukemia Non- Hodgkin's Lymphoma Corpus 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 5
  • Trend of cancer in Jordan, 19802010
  • Ten most common cancers among Jordanian Males, 2010 Rank 1 2 3 4 5 6 7 8 9 10 Cancer No % Colorectal 332 14.2 Lung 311 13.3 Prostate 218 9.4 U.Bladder 186 8 Leukemia 127 5.5 Non- Hodgkin's Lymphoma 120 5.2 Brain & CNS Stomach 106 4.5 90 3.9 Larynx 74 3.2 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 3 136 5.4 4 Thyroid Non-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 & Adjuvant Temozolomide for Glioblastoma 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 987996
  • Introduction Treatment of Glioblastoma Surgical resection ,safely feasible Adjuvant Radiotherapy adjuvant carmustine, (a nitrosourea drug ) used in the USA . 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 Treatment of recurrent gliomas Temozolomide as a single agent Antitumor activity reduces the DNA-repair enzyme (MGMT) in tumor tissue longer survival especially patients with glioblastoma Hegi ME, et al.. Clin Cancer Res 2004;10:1871-1874
  • Introduction pilot phase 2 trial in patients Glioblastoma Concomitant: temozolomide + fractionated radiotherapy adjuvant Temozolomide 6 cycles two-year survival rate, 31 % promising clinical activity Stupp R et al.. J Clin Oncol 2002;20:1375-1382
  • therefore the (EORTC) & the (NCIC) initiated this trial Concomitant: temozolomide + fractionated radiotherapy adjuvant Temozolomide 6 cycles phase 3 trial in patients Glioblastoma Comparing Radiotherapy alone
  • the (EORTC) & the (NCIC) trial patients The median age : 56 years 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 84% underwent debulking surgery 573 patients from 85 institutions in 15 Countries pathological review confirmed in 93 % Histologic slides were submitted for 85%
  • the (EORTC) & the (NCIC) trial Methodology & Design 573 patients from 85 institutions in 15 Countries From August 2000 until March 2002 Radiotherapy (286 patients) Randomly assigned to receive End point : Overall survival Radiotherapy +temozolomide (287 patients)
  • the (EORTC) & the (NCIC) trial treatment - Radiotherapy alone Radiotherapy 60 Gy/ 30 fractions /6 weeks day 1 7 5 14 21 28 35 43 week 1 week 2 week 6 week 3 week 5 week 4 GTV (tumor without edema ) CTV (GTV+ 2-3 cm margins) Planned with CT-scan + 3D planning system Radiotherapy delivered with 6MV linear & more
  • the (EORTC) & the (NCIC) trial treatment - RTx+Temodal Radiotherapy 60 Gy/ 30 fractions /6 weeks day 1 7 5 14 21 28 35 43 week 1 week 2 week 6 week 3 week 5 week 4 GTV (tumor + edema ) CTV (GTV+ 2-3 cm margins) Planned with CT-scan + 3D planning system Radiotherapy delivered with 6MV linear & more
  • the (EORTC) & the (NCIC) trial treatment - RTx+Temodal Radiotherapy 60 Gy/ 30 fractions /6 weeks day 1 7 5 14 21 28 Break 35 43 week 1 Temodal 75 mg/m2 Daily 7 D week 2 Temodal 75 mg/m2 Daily 7 D week 6 week 3 Temodal 75 mg/m2 Daily 7 D week 5 week 4 Temodal 75 mg/m2 Daily 7 D Temodal 75 mg/m2 Daily 7 D Temodal 75 mg/m2 Daily 7 D 4 week Adjuvant Temodal Temodal 5 days every 28 days for 6 cycles 150 mg/m2 cycle 1 200 mg/m2 cycle 2 200 mg/m2 cycle 3 200 mg/m2 cycle 4 200 mg/m2 cycle 5 200 mg/m2 cycle 6 GTV (tumor without edema ) CTV (GTV+ 2-3 cm margins) Planned with CT-scan + 3D planning system Radiotherapy delivered with 6MV linear & more
  • the (EORTC) & the (NCIC) trial Results At a median follow up 28 months 480 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 progressionfree survival was: RTx alone : 5.0 months RTx+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 adjuvant  During concomitant temozolomide therapy 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 O6methylguanine-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-ofprinciple 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 1stline T/RT significantly improves ORR. The rate of confirmed PsPD was low in both arms. Clinical trial information: NCT00943826
  • Conclusion Thank you