Recent advances in Glioblastoma Multiforme Management


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Recent advances in Glioblastoma Multiforme Management

  1. 1. Recent Advances in High Grade Gliomas (HGG) Dr Rajesh B Associate Professor Department of Radiotherapy Christian Medical College, Vellore
  2. 2. Learning Objectives • Current management strategy for High Grade Gliomas • Radiotherapy treatment planning guidelines for High Grade Gliomas • Chemo irradiation for HGG - How to titrate dose of TMZ during RT • How to assess response for Gliomas – RANO Guidelines • Recent advances in RT /chemo for HGG • Clinical trials which would answer our queries in Future
  3. 3. Objectives of Radiation in Malignant Glioma • Potential for cure • Prolong survival times with improved quality of life • Control local infiltration of cancer cells • Palliation Overall, the objectives of radiation in the treatment of CNS malignancies include:
  4. 4. Current management strategies in HGG
  5. 5. Treatment Algorithm for management of GBM
  6. 6. Radiotherapy treatment planning guidelines for HGG
  7. 7. Simulation Process • Simulate after removal of Craniotomy Staples / Sutures • Start RT within 4-6 weeks of surgery • An immobilization mask is fashioned to reduce motion during and between fractions. • The planning CT scan is extended to encompass the head and neck region (Atleast upto C4 levels) to allow sufficient anatomic areas for proper image fusion and genera-tion of high- quality digitally reconstructed radiographs (DRRs) and to permit the introduction of noncoplanar beams; • Slice Thickness for CT images – 2.5 - 3mm • Do MR Fusion for good TV delineation
  8. 8. Radiotherapy Volumes for HGG’s Planning Target Volume (PTV) - To account for both organ motion and setup error - Organ motion in the brain is minimal (e.g., <1 mm) - Modify PTV to exclude normal tissue in areas where gliomas are unlikely to infiltrate.
  9. 9. Tips for Planning • Check the critical organ delineation carefully • Check BEVs • Avoiding entrance and exit dose to the eye may be a relatively simple means of preventing not only cataracts but also conjunctivitis and a dry eye • Contour the ear canals, as there is now a greater awareness of the risks of developing otitis externa as well as otitis media • For tumors located in the temporal lobes, the exit dose to the parotid gland may bring about xerostomia. • Always contour Brain tissue outside the PTV as a organ and try to limit dose to the same as low as achievable. • Use functional MRI or MRS data if available for planning purposes
  10. 10. • RT dose prescription as per RTOG guidelines. • A clinical judgment was made to modify the planning target volume to exclude sensitive structures by presuming that „„natural barriers‟‟ would impede the contiguous spread of tumor cells. • As such, the traditional 2–2.5-cm margin was not added in the direction of the temporal bone.
  11. 11. Dose constraints to critical organs
  12. 12. Hippocampus contouring
  13. 13. Hippocampus delienation by software Courtesy : Dr Minesh Mehta
  14. 14. Chemoirraditation for HGG
  15. 15. ChemoRT schedule • RT - Five fractions per week • Prophylactic antiemetics • PCP prophylactics • Low dose steroids with H1 blocker • Weekly blood counts • Give Temozolomide for a maximum of 49 days and then STOP
  16. 16. Dose modification for Concomittant Temozolomide
  17. 17. Dose Level Dose (mg/m2/day) Remarks -1 100 Reduction for prior toxicity 0 150 Dose during Cycle 1 1 200 Dose during Cycles 2-6 in absence of toxicity Toxicity Reduce TMZ by 1 Dose Level* Discontinue TMZ Absolute Neutrophil Count < 1.0 x 109/L (< 1000) See footnote† Platelet Count < 50 x 109/L (<50,000) See footnote† CTC Nonhematological Toxicity (except for alopecia, nausea, vomiting) CTC Grade 3 CTC Grade 4† †TMZ is to be discontinued if dose reduction to < 100 mg/m2 is required or if the same Grade 3 nonhematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction. TMZ=temozolomide; CTC=Common Toxicity Criteria. Dose modification for Adjuvant Temozolomide
  18. 18. Response Assessment for HGG
  19. 19. RANO Basics The Revised Assessment in Neuro-Oncology (RANO) criteria was published in 2010, as an update to the existing MacDonald criteria (see references at end) • Used for assessing disease progression and treatment response in glioblastoma multiforme (GBM) References Print Version: “Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Working Group.” Journal of Clinical Oncology. 2010 Apr 10; 28(11):1963-72. Online Version:
  20. 20. Image Acquisition •MRI is the only modality used to assess response and progression •Minimum sequences required: – Pre-contrast T1, T2/FLAIR – Post-contrast T1, with two orthogonal planes (or a volume acquisition) recommended •Recommended slice thickness ≤5 mm with no gap •Additional imaging that may be helpful: – Diffusion (DWI, ADC)
  21. 21. Definitions Measurable lesions Contrast enhancing lesions Minimum size: two perpendicular diameters ≥10 mm If slice + gap thickness >5 mm, minimum size is 2 times the total Do not include cavity, cyst, or necrosis in the measurement Non-measurable lesions Lesions that are too small (e.g. 12 x 8 mm) Lesions that do not enhance (seen only on T2/FLAIR) Lesions with a poorly defined margin
  22. 22. Pseudoprogression • Enhancement that simulates tumor growth, most often caused by radiation (whole brain or focal) • Growth of existing lesions or appearance of new lesions within 12 weeks of completion of radiation therapy may be the result of treatment effects rather than growth of tumor. • Clinically the neurological status of the patient would be stable / improved • Continued follow-up imaging can determine whether initial lesion growth was true progression or pseudoprogression. – If lesion continues to enlarge, the initial growth is called true progression – If lesion stabilizes or shrinks, the initial growth is confirmed as pseudoprogression • In such cases, the baseline SPD is no longer included when choosing the nadir value for the purposes of determining when progression occurs • Diffusion weighted imaging can help distinguish pseudoprogression from true tumor growth, but its use is still experimental. • The use of MR perfusion and spectroscopy is also being explored.
  23. 23. Recent advances in Chemotherapy & Radiotherapy management of HGG
  24. 24. Positive Phase III Trials Evaluating the Role of Irradiation, Chemotherapy, or Chemoradiation in the Treatment of Malignant Gliomas
  25. 25. Methylation status as a Prognostic marker
  26. 26. Methylation status as a Prognostic marker
  27. 27. RTOG-0525- Dose intense Vs Conventional Schedule in Adjuvant therapy
  28. 28. Treatment Plan ChemoRT: Focal RT ( 60 Gy /30 #, Conc TMZ 75 mg/m2) followed by 6 cycles of adjuvant TMZ Adjuvant chemotherapy: (Both arms – six cycles of 28 days) Group A : Dose Dense - 150 mg/m2 daily days 1 to 7 and 15 to 21 of each cycle Group B: Metronomic Arm- 50 mg/m2 daily days 1– to 28 of each cycle Antiemetics / Supportive care inculding Growth factor support at discretion of physician Maintenance doses of 13-cis-retinoic acid - 100 mg/m2 daily days 1 to 21 of a 28-day cycle till PD. Dose Dense Vs Metronomic Schedule in Adjuvant therapy for GBM
  29. 29. Control : Focal RT ( 60 Gy /30 #, Conc TMZ 75 mg/m2) followed by 6 cycles of adjuvant TMZ Trial Group: 2 cycles neoadjvuant chemotherapy ACNU (40 mg/m2/day) and CDDP (40 mg/m2/day) CI 72 hrs Q6 weeks Followed by RT and Adj TMZ as in control group Median survival Overall survival 1yr 2yr Control 18.9 m 81.7% 27.8% Treatment 28.4m 72.4% 50.9% Study stopped inbetween due to 30% Grade 4 toxicty of the neoadjvuant arm
  30. 30. RTOG 9305: Newly Diagnosed GBM Stereotactic Radiosurgery Phase III Trial Arm 1 RT – 60Gy / 30 # BCNU 80mg/m2 D1-3 of RT then Q8weeks for 6 cycles Arm 2 SRS followed by RT – 60Gy / 30 # BCNU 80mg/m2 D1-3 of RT then Q8weeks for 6 cycles SRS Dose 24Gy – Lesion < 2cm 18 Gy- Lesion 2.1 -3 cm 15 Gy – Lesion 3.1-4 cm
  31. 31. • For patients with malignant glioma, there is Level I-III evidence that the use of radiosurgery boost followed by external beam radiotherapy and BCNU does not confer benefit in terms of overall survival, local brain control, or quality of life as compared with external beam radiotherapy and BCNU. • The use of radiosurgery boost is associated with increased toxicity. • For patients with malignant glioma, there is insufficient evidence regarding benefits / harm of using – radiosurgery at the time progression or recurrence. – stereotactic fractionated radiation therapy in patients with newly diagnosed or progressive/recurrent malignant glioma
  32. 32.
  33. 33. Results of Irradiation of CSC Niches In the human brain, the 3-5 mm thick lateral periventricular region of the lateral ventricles - the subventricular zone (SVZ ) - and a subsection of the hippocampal formation - the subgranular layer ( SGL ) – have been shown to harbor normal brain stem cells These regions are believed to contain specific regions of so-called stem cell niches, which support neuronal stem cells and keep them in an undifferentiated state .
  34. 34. Hypofractionated IMRT with Field in Field Boost for Newly diagnosed GBM CT – MRI fusion done ( Post op MRI) Combination of coplanar and noncoplanar beams GTV = CE tumor on T1W + Entire resection cavity CTV = Edema visible on T2-weighted MRI images TV i = GTV + CTV + 1 cm TV b = GTV + 0.5 cm 5mm minimum margin to spare critical normal OARs
  35. 35. Results of Hypofractionated IMRT • Median OS – 13.6 months (Range – 0.9-40.2 months ) • Median PFS – 6.5 months (Range – 0.9-40.2 months ) • 1yr survival – 57 % • 2yr survival – 19% • No difference in OS among dose groups
  36. 36. Accelerated Hypo IMRT with TMZ • Total of 35 patients ( 74% pats in old RPA Class 5 or 6) • Patients whose tumors were within 1.5 cm of either the optic chiasm or the brainstem were not included • The GTV was defined as the surgical cavity and/or postoperative contrast- enhancing lesion on MRI fusion. • The PTV was taken as the GTV plus a 1.5-cm margin. Visible edema outside the PTV margin was not included in the volume. • Treatments were delivered with an isocentric technique, often with three or more non coplanar beams. • GTV - 60 Gy in 20 daily 3-Gy fractions – 95–100% isodose line covered the GTV – 65–70% line encompassed the PTV (40Gy in 20 daily fractions) • Concomitant TMZ at a dose of 75 mg/m2 daily during hypo-IMRT, followed by adjuvant TMZ at a dose of 150–200 mg/m2 daily for 5 days every 28 days, according to the EORTC/NCIC regimen
  37. 37. Results of Accelerated HypoIMRT trial • Median follow-up - 12.6 m. • 82.8% - completed CRT and 71.4%- received a median of four cycles of adjuvant TMZ. • Median OS - 14.4 m • Median DFS - 7.7 m
  38. 38. Elderly GBM – NOA-08 / Methvsalem Trial (Age >65yrs) Inclusion criteria: Age >65 yrs Median Survival: RT 9.8 mo TMZ 8.6 mo Hazard ratio 1.28 (0.94-1.63) TMZ alone inferior to RT Unexpected toxicity in elderly
  39. 39. Elderly GBM – Nordic Trial (Age >60yrs) Temozolomide may be an alternative to RT
  40. 40. Recursive Partioning Analysis of GBM
  41. 41. MRS Study for Volume delineation in our institute
  42. 42. MRS based volume delineation • Multivoxel MRS was done at various levels on the FLAIR sequences. – At levels of enhancing component that contains enhancing lesion – Surrounding enhancing edema – Regions with non enhancing edema alone and – Areas with normal brain. • Peak parameters for choline, creatine, NAA, lipid and lactate was estimated on a voxel by voxel basis and the choline-creatine index (CCI) and Choline-NAA index (CNI) was defined. • At these image levels, following areas were defined on a voxel by voxel basis – Choline Creatine Index of more than 1.5 – Choline NAA Index (CNI) of more than 3 – CNI of 1.5 to 3 and CNI of less than 1 was defined
  43. 43. • Areas with CNI more than 3 and those areas with CNI between 1.5 and 3 were defined on a voxel by voxel basis. The parameters defined at these image levels on which MRS was performed, was extrapolated to other images of FLAIR MRI on which MRS was not performed. • The three dimentional MRS volume defining the high risk area encompassing CNI of more than 3and intermediate risk area encompassing CNI of 1.5 to 3 was compared with the volume defined by post Gadolinium T1W and T2W FLAIR sequences. • Disjoint and conjoint volumes were then defined by comparing the volumes defined by the MRI alone and combined MRI & MRS. Similar comparison was made between volumes defined by areas encompassing CNI less than 1.5 and non enhancing edematous component on FLAIR MRI.
  44. 44. MRI VOLUMES MRS VOLUMES T1W GTV ( Enhancing component on T1W image) CNI of more than 3 T2W GTV (Enhancing component on T2W FLAIR image) CNI of 1.5 to 3 and CCI more than 1.5 PTV (GTV + 2.5 cm uniform margin) CNI less than 1.5 + 5 mm MRS analysis for volume delineation was done later than the MRI and hence the MRS data was not utilized for treatment of these patients . Treatment planning of all patients were done as per CT-MRI based volume delineation. This study was only a dosimetric study and volumes generated using MRS was not used to treat these patients
  45. 45. Comparison of T2 FLAIR GTV volume (cc) to MRS defined GTV Volume [Intermediate Risk area (CNI 1.5)
  46. 46. Comparison of PTV volume in MRI (GTV T2 FLAIR+2.5 cm) and PTV in MRS (CNI< 1.5+ 5 mm) Wilcoxon signed-rank test: Adjusted variance = 96.25 z = 2.803 P = 0.0051
  47. 47. Picture below Depicts the Conjoint T1 GTV Volume (Blue) of MRI in a patient with Glioblastoma that is much less than the corresponding High Risk Area (Brown) in MRS seen as disjoint area The pictures shows the conjoint and disjoint PTV volumes of MRI and MRS MRI defined PTV (dark) extends into the orbit whereas the extension is not seen in the PTV defined by MRS.
  48. 48. Clinical trials that would answer our questions
  49. 49. Major ongoing Trials in High Grade Gliomas
  50. 50. CATNON: Phase III trial comparing no adjuvant chemotherapy versus adjuvant therapy until progression for anaplastic glioma without 1p/19q loss
  51. 51. CODEL : Phase III Intergroup Study in Newly Diagnosed Anaplastic ODG or Anaplastic Mixed Glioma with Chromosomal cowith co--deletions of 1p and 19q.
  52. 52. Trials of anti-angiogenic agents for newly-diagnosed glioblastomas • VEGF – Bevacizumab (RTOG, Roche) – Aflibercept (VEGF VEGF-Trap) (ABTC) • VEGFR – Cediranib (VEGFR, PDGFR) – Vandetanib (VEGFR, EGFR) – Sorafenib (VEGFR, PDGFR, Raf) – XL184 (VEGFR, Met) (Exelixis) – Pazopanib (VEGFR, PDGFR, cKIT) • PKCβ – Enzastaurin (UCSF, multiple) • Integrins – Cilengitide (Merck KG)
  53. 53. TMZ/RT ±Cilengitide in MGMTmethylated GBM CENTRIC/EORTC 26071 / 22072
  54. 54. BRAIN Study Design – Recurrent GBM Avastin ± Irenotecan
  55. 55. AVAglio study or RTOG-0825
  56. 56. • Longest documented GBM patient in Literature -20 yrs • He had been treated with surgery and partial brain irradiation (59 Gy of 6- MV photons in conventional fractionation delivered via the shrinking-field technique). • The authors speculated that the outcome may have stemmed from the fact that he had a favorable molecular profile (e.g., methylated MGMT promoter, PTEN positive, and TP53 positive, which the authors termed “triple positive” similar to the nomenclature of breast cancer). • 5 yr survival in GBM from the EORTC-NCIC - 10%, and • 5 yr survival for pts with favorable prognostic factors ~ 30%
  57. 57. Thank You