High grade glioma, standard of care & new advances..

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Aim of this ppt presentation:
To understand the standard of care for both GBM and anaplastic glioma.
To know what is the new advances and modifications to the standard of care?
Contents:
Introduction: 2 slides.
GBM:
Epidemiology: 1 slide.
Molecular biology & New trends: 5 slides
EORTC/NCIC trial: 10 slides.
MGMT: 1 slide.
Evidence-based medicine: 6 slides.
Avastin in GBM: 2 slides.
Novocure (TTF): 2 slides.
Gliadel (BCNU) wafers: 1 slide.
Anaplastic astrocytoma: 7 slides
Take home message.

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High grade glioma, standard of care & new advances..

  1. 1. By Osama Elzaafarany Assistant lecturer of clinical oncology Medical Research Institute-Alexandria University High-grade glioma.. Standard of care & new advances… March 2014
  2. 2. Contents:  Introduction: 2 slides.  GBM:  Epidemiology: 1 slide.  Molecular biology & New trends: 5 slides  EORTC/NCIC trial: 10 slides.  MGMT: 1 slide.  Evidence-based medicine: 6 slides.  Avastin in GBM: 2 slides.  Novocure (TTF): 2 slides.  Gliadel (BCNU) wafers: 1 slide.  Anaplastic astrocytoma: 7 slides  Take home message. Aim of this presentation: • To understand the standard of care for both GBM and anaplastic glioma. • What is the new advances and modifications to the standard of care?
  3. 3. WHO grade III grade IV What is high- grade glioma? GBM • Anaplastic astrocytoma • Anaplastic oligodendroglioma • Anaplastic mixed glioma “oligo-astrocytoma” Anaplastic gliomas
  4. 4. Glioblastoma Multiforme: ‫ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬  Most common 1ry malignant brain tumor in adult.  About 50 % of all gliomas.  1 year survival about 30 %.  Men > females.  Peak incidence: 65-75 ys.  Age median survival.  Malign CNS = 1.4% of all cancers.  1ry CNS tumors ~ 66.000 new cases/year: (USA, 2012): => glioma = 32 % => GBM = 16% of 1ry CNS Ts. ~10.000 new cases of GBM/year Established risk factor: previous exposure to ionizing radiation: Pre-natal diagnostic X-rays. Cranial RTx for ALL: (risk 0.5% at 10ys). • Hereditary syndromes: 5% of GBM cases: • Suspected when you have multiple brain tumors. • P53, NF1, Turcot’s.
  5. 5. Molecular Biology:  GBM characterized by extensive heterogeneity at the cellular and molecular levels.  Develops either de novo (primary GBM), or as the result of the malignant progression from a lower-grade glioma (secondary GBM).  4 molecular sub-types: (classical, mesenchymal, proneural and neural)  The true cellular origin of gliomas, including GBM, is still a debatable question => Two different hypotheses for the origin:  accumulation of alterations that occur in differentiated mature cells (glial cells).  most recent hypothesis assumes that cancer cells arise from the accumulation of alterations that occur directly in stem cells: CD133 +ve. treatment resistance treatment resistance
  6. 6. Molecular Biology: Growth factor receptors Signaling pathways  RB pathway.  P53 pathway.  Tyrosine Kinases pathways: RAS-RAF. PI3K
  7. 7. Molecular Biology “promising agents” EGFR 1) Over-expressed: 50% of GBM. 2) Del of exon 2-7 “loss of extra-cell domain”: (mutant EGFRvIII) • 30 % of patients • Poor prognosis. • Celldex intradermal vaccine (Rindo pepi mut). • Phase II study, ACT III trial, SNO 2010, 65 pts with newly diagn GBM, • Taken for 3 months with adjuv TMZ. • Median survival ~ 22 ms (compared with 15 m in EORTC/NCIC study) Now ongoing: Phase III Study of Rindopepimut/GM-CSF in newly Diagnosed GBM; (ACT IV). ClinicalTrials.gov Identifier: NCT01480479
  8. 8. Cilengitide: • Anti-integrins: which is important for angiogenesis. • I.V. drug. • Newly diagnosed GBM:  Phase II trial, (Burt Nabors, Cancer2012;118:5601-7, Nov 2012)  Combined with RT + TMZ.  OS was ~20 months.  Patients with MGMT promoter methylation tend to show a higher PFS and OS (~30 ms). • Now ongoing:  CORE study, phase II (NCT00813943)  Clinical trial testing the efficacy of cilengitide with TMZ + RT in patients with or without MGMT methylation.
  9. 9. Cediranib: • Oral pan-VGEFR TKI • Recurrent GBM:  As a single agent (phase II): showed a PFS ~ 4 ms and OS was ~ 7.5 ms  A phase III trial with cediranib + lomustine for the treatment of recurrent GBM in currently ongoing (NCT00777153). • Newly diagnosed GBM:  All clinical trials are currently ongoing or recruiting:  Phase I/II cediranib + RT + TMZ (NCT01062425 and NCT00662506);  Phase I combination with BVZ (NCT00458731);
  10. 10. What is the standard of care for GBM? adjuv. ConcurrentSurgery RTx TMZ TMZ Age ≤ 70 PS ≤ 2 Surgery: max safe resection. RTX: 60 Gy, fractionated, partial brain. TMZ: Temodar.
  11. 11. EORTC/NCIC
  12. 12. EORTC/NCIC RAND After Surgery • 573 pts. • GBM. • Age ≤ 70 • PS ≤ 2 RTX alone RTx+TMZ then adjuv TMZ
  13. 13. EORTC/NCIC methodology:  Radiotherapy :fractionated focal irradiation ,2 Gy per fraction given once daily 5 days per week over 6 weeks; (total dose of 60 Gy).  Concomitant chemotherapy: temozolomide 75 mg /m2 daily. from the first day of radiotherapy until the last day, (no longer than 49 days).  Adjuvant temozolomide: 6 cycles of 5-day schedule every 28 days; 150 mg /m2 for the first cycle and was increased to 200 mg /m2 beginning with the second cycle.  patients in the radiotherapy plus temozolomide group were to receive prophylaxis against Pneumocystis carinii pneumonia, consisting of either inhaled pentamidine or oral trimethoprim– sulfamethoxazole
  14. 14. •At least 2 weeks of Cortz. Before randomization. •About 70% were on Cortz. About 16% had just Biopsy.. About 70% were ≥ 50 years subgroup with no survival benefit
  15. 15. EORTC/NCIC Results: 2-year survival rate 27 % with RTx + TMZ 10 % with RTx alone. 5-years: 10.9 % 5-years: 1.9 % Median survival benefit=2.5 m; From 12.1 m to 14.6 m with RTx-TMZ
  16. 16. TMZ did not increase risk of treatment delay or interruption Median time from diagnosis to the start of treatment was 5 weeks 85 % completed concurrent RTx-TMZ 78% started adjuv TMZ 47% completed 6 cycles Main reason was disease progression
  17. 17. EORTC/NCIC Results:  Grade 3 or 4 hematologic toxic effects: • Concomitant RTx + TMZ: 7 % of patients. • RTx alone: 0 % • Adjuvant TMZ: 14 %  A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60–70 years.  Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy
  18. 18. Critic: Benefit from Concomitant RTx-TMZ Adjuvant TMZ OR
  19. 19. MGMT  O-6-methylguanine-DNA methyltransferase.  DNA repair enzyme.  Function: repair the damage of DNA caused by alkayting agents e.g TMZ.  When methylated: it dose not work.  Methylated cases: better response to TMZ, better PFS and OS.  This was illustrated in the update of EORTC/NCIC trial in 2009, and both NOA-08 and the Nordic trial of TMZ in elderly GBM pts.
  20. 20. Evidence- based medicine: ConcurrentSurgery TMZ RTx TMZ
  21. 21. ConcurrentSurgery TMZ RTx TMZ Benefit of RTx : Dose of RTx : Fx of RTx : Stereo. boost: Dose-dense TMZ Avastin BTSG MRC RTOG9006 RTOG9305 RTOG0825 AVAglio GLARIUS RTOG0525 Old age Nordic NOA-08 Canadian Frensh Evidence- based medicine: BCNU-wafer Neuro-onc J 2003, Phase III
  22. 22. BTSG, 1978: ‫ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬ MRC, 1991: 474 pts randomized to 45 Gy vs 60 Gy increase surv from ( no chemo) 9 to 12 ms. With 60 Gy ‫ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬ RTOG9006, 1998: 222 pts. 90% GBM RAND • Observ. • BCNU. • RTx alone. • RTx +BCNU. Increase surv: 3-6 ms 712 pts. RAND • 60 Gy: (2Gy/Fx) • 72 Gy: (1.2Gy BID) Better survival
  23. 23. RTOG0525, 2011-JCO: 823pts. KPS≥60 RAND • Standard TMZ dose • Dose-dense TMZ. No difference in both OS & PFS. Increase toxicity with dose- dense After RTx
  24. 24. Canadian trial, 2004-JCO: ‫ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬ French trial, 2007-NEJM: 100 pts. GBM age≥ 60 KPS≥ 50 RAND •RTx 60 Gy. • 40 Gy/ 15 Fx (3 Ws) Same OS ; 5.5 ms. decrease need to inc Cortz dose with 40 Gy 85 pts. G III & IV age≥ 70 KPS≥ 70 RAND • RTx (50 Gy/ 1.8 Gy) •BSC Significant inc of survival Critic: underpowered statisticaly GBM in elderly more than 44% of GBM occcur in pts > 65 ys.
  25. 25. Nordic (NCBTSG), 2012-Lancet onc: ‫ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬ German (NOA-08), 2012-Lancet onc : “non-inferiority study” 342 pts. GBM Age > 60 Good PS RAND TMZ alone; 6 ms vs RTx 34 Gy/ 2Ws vs RTx 60 Gy. 412 pts. GBM (89%) Age > 65 KPS≥ 60 RAND • RTx (60Gy/ 30 Fx) •TMZ: Week on / week off 100 mg / m2 No Significant differences in OS (~9 ms) GBM in elderly > Neutopenia in TMZ arm Better survival when compared to 60 Gy
  26. 26. Avastin in GBM FDA approval in recurrent cases in 2009 based on 2 phase II studies: BRAIN trial, JCO 2009:  Phase II.  167 pts with Recurrent disease.  Avastin alone or with Irinotecan.  Avastin decreases the need to escalade the cortz dosage.  Intra-cranial Hge 4% with Avastin + Irino.  Grade ≥ 3: HTN (8%), convulsion (6%), fatigue (90%). 6ms PFS OS RR Avastin 43 % 9 % 28 % Avastin+Irinotecan 50 % 9 % 38 %
  27. 27. Avastin in newly diagnosed GBM Adding to standard of care Compared with standard of care GLARIUS trial • JCO, 2013, Abstract • Phase III • ~ 170 pts. • Non-methyl MGMT Significant inc In PFS with Avastin + Irinotecan+RTx vs Standard of care AVAglio trial • JCO, 2013, Abstract • Phase III • ~900 pts. Significant inc In PFS with addition of Avastin to Standard of care RTOG 0825 • JCO, 2013, Abstract • Phase III • 637 pts. Significant inc In PFS with addition of Avastin to Standard of care Inc GIII toxicity with Avastin.
  28. 28. Novocure (TTF): • Uses electric fields within the human body that disrupt the rapid cell division exhibited by cancer cells. • Disrupt mitotic spindle microtubule assembly and to lead to dielectrophoretic dislocation of intracellular macromolecules and organelles during cytokinesis. •Affect only one cell type at a time; The frequency used for a particular treatment is specific to the cell type being treated. • TTF therapy has not been shown to affect cells that are not undergoing division.
  29. 29. Novocure (TTF): ‫ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬  FDA approval in 2011 for recurrent cases of GBM based on phase III study:  Stupp et al, Eur J cancer, 2012  237 pts with recurrent disease.  Rand to TTF vs Chemo.  Result was same survival.  Low toxicity with TTF + imroved QOL.  Now ongoing trial for adding TTF to standard of care in newly diagnosed cases. (NCT00916409)
  30. 30. Gliadel wafers: • Implantation of BCNU-wafers in the surgical cavity intraoperatively. • Significantly improve survival in recurrent cases (Brem et al, Lancet 1995). • In a phase III trial from Germany, which was published at the neuro-oncology journal in 2003, 240 newly diagnosed pts showed significant improvement in median survival from 12 m to 14 ms after implantation of BCNU-wafers then RTx ( no adjuv systemic chemo). • FDA approved in new cases. •Toxicity:  CSF leak 5%  I.C.HTN 9 %. . Which is not the standard of care
  31. 31. Anaplastic Gliomas ‫ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬ Anaplastic astrocytomas, anaplastic oligodendrogliomas, and anaplastic oligoastrocytomas. Would you treat it typically as the GBM ??
  32. 32.  Resection appears to improve survival relative to biopsy, as it does for GBM.  Addition of chemo to Rtx. failed to improve survival in 2 phase III trials: (unlike GBM)  Co-deletion of 1p 19 q correlates with better response to chemo.  Adjuvant temozolomide was as effective and less toxic than PCV in anaplastic astrocytoma, based on one retrospective study. (?) Rationale for the ongoing CODEL trial. RTOG 9402 and EORTC 26951 Rationale for the ongoing RTOG 9813 trial. Should be investigated in pts with poor prognosis ( non co-deleted): Rationale for the ongoing CANTON trial. What bout using CTx. alone as adjuvant ?
  33. 33. RTOG9402, 2006-JCO : after surgery ‫ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬ EORTC26951, 2006-JCO: after surgery 289 pts. Anaplastic oligodendr. RAND PCV X 4 then Rtx. RTx alone (60Gy) Same OS PCV increase PFS Benefit with co-deleted pts. 368 pts. Anaplastic oligodendr. RAND • RTx then PCV X 6 •RTx alone (60Gy) No diffr. in OS Increase PFS
  34. 34. NOA-04, 2009-JCO: • Survival rates were equivalent whether chemotherapy or radiotherapy was used first among patients with anaplastic astrocytomas, oligodendrogliomas, and mixed tumors. • Time to progression following RT was longer than after chemotherapy. • Initial radiation therapy achieved more complete and partial responses than initial chemotherapy. 318 pts. Anaplastic glioma RAND • RTx •PCV •TMZ Progression • Chemo. •RTx •RTx Suggesting the superiority of radiotherapy.
  35. 35. The ongoing CATNON (Concurrent vs. Adjuvant Temozolomide for NON 1p19q co-deleted anaplastic gliomas) It will answer 2 questions: • Benefit of add CTx in non co-del anaplastic glioma. • Concurrent vs adjuv TMZ (? In EORTC/NCIC trial).
  36. 36.  CODEL; (for 1p/19q CO-DELeted tumors): Randomizes patients to:  RT alone.  RT with concurrent and adjuvant temozolomide.  Temozolomide alone. To prospectively address the issue of CTx alone in co-deleted patients.  RTOG 9813 : Randomized patients with anaplastic astrocytomas (or oligoastrocytomas) to:  Radiotherapy with concurrent nitrosourea; (carmustine or lomustine).  Radiotherapy with concurrent temozolomide.
  37. 37. What is the standard of care for anaplastic glioma ? Surgery RTx TMZ PCV Surgery: max safe resection. RTX: 60 Gy, fractionated, partial brain. PCV: Procarbazine+CCNU+Vincristine If co-deleted or concurrent Good PS Before or after RTx.
  38. 38.  The standard of care of newly diagnosed GBM cases is Surgery then concurrent RTX/TMZ then adjuvant 6 cycles TMZ.  Some new and promising trends will be based on molecular targets.  The standard of care of newly diagnosed anaplastic glioma cases is surgery followed by adjuvant RTx, and if co-deleted you can add adjuvant chemo.

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