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Workshop on Advanced Technologies in Radiation Oncology

Workshop on Advanced Technologies in Radiation Oncology. Minesh Mehta. Principal “Dose-Limiting Toxicity” Brain Tumors. Necrosis rates of ~5% starting at 60 Gy. 72 Gy with altered fractionation Visual damage of ~1-3% starting at >54 Gy. Endocrine damage starts at ~45 Gy.

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Workshop on Advanced Technologies in Radiation Oncology

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  1. Workshop on Advanced Technologies in Radiation Oncology Minesh Mehta

  2. Principal “Dose-Limiting Toxicity”Brain Tumors Necrosis rates of ~5% starting at 60 Gy. 72 Gy with altered fractionation Visual damage of ~1-3% starting at >54 Gy. Endocrine damage starts at ~45 Gy. Neurocognitive damage: Depends on what you measure, when, & age Cochlear dysfunction starts at >50 Gy

  3. Evidence Levels • Logically, few of the toxicity data come from phase III trials with toxicity endpoints. • Most come from phase I trials, or “institutional experiences” • Numerous variables need to be teased out separately, e.g., age, volume, fractionation, comorbidities, other therapies, etc.

  4. An example of a phase III trial: RTOG 9006: 60 vs. 72 Gy for GBM

  5. Further Dose Escalation: Necrosis • CCG BSG Trials went upto 78 Gy (1 Gy bid) • U Mich 3 D Trials went upto 90 Gy with reduced volumes • Recent RTOG 3D dose-escalation trial (9803): • PTV2 < 75 cc: escalated to 84 Gy (n = 95) • PTV2 > 75 cc: escalated to 84 Gy (n = 109) • * Toxicity not graded: found from central review • † Number of patients with late toxicity data

  6. An Example: Risk of Dementia with WBRT for Brain Metastases • Retrospective study of 47 patients one-year survivors treated at MSKCC • 5/47 (11%) patients treated with WBRT developed severe dementia: 6 Gy x 3, 4 Gy x 3 5 Gy x 3, 3 Gy x 5 5 Gy x 3, 3 Gy x 4 6 Gy x 3, 4 Gy x 3 + adria analog 3 Gy x 10 + radiosensitizer • 0f 15 patients treated with <3 Gy/fx, 0 had dementia Dementia associated with high-dose fractions. DeAngelis LM, et.al. Neurosurgery 1989;24:798-805.

  7. Can SRS or SRT reduce toxicities? • Few direct comparisons exist • Significant dose-escalation can be achieved • In general, necrosis rates remain under 5% • However, only small volumes are generally treated • For long-term toxicity, benign tumors need to be studied and these are generally not included on any clinical trials, e.g. meningioma, vestibular schwannoma, etc.

  8. RTOG 90-05: Phase I SRS trial • 156 patients with rec CNS tumors < 40 mm diameter • SRS dose by size • For < 20 mm tumors, dose not escalated > 24 Gy

  9. An example of a phase III trial: RTOG 9305: SRS boost for GBM • 60 Gy + BCNU +/- SRS boost (15-24 Gy) • 186 analyzable patients • 4 vs 0 G3 late neuro toxicity in SRS arm • QOL comparable (Spitzer) • MMSE comparable • Quality-adjusted survival comparable

  10. RTOG 9508: QOL, Toxicity * Significantly lower steroid dependence on RS arm No difference in outcome by technique, Linac vs. Gamma Knife

  11. VS Radiosurgery vs FSRT

  12. Dose, Length & Complications Flickinger, IJROBP

  13. Probability of Serviceable Hearing Andrews et al, Int J Rad Onc Biol Phys 50:1265-1278, 2001

  14. Intensity Modulated RT

  15. INTENSITY MODULATED RADIATION THERAPY VERSUS THREE DIMENSIONAL CONFORMAL RADIATION THERAPY FOR THE TREATMENT OF HIGH GRADE GLIOMA: A DOSIMETRIC COMPARISON Shannon M MacDonald1, Salahuddin Ahmad2, Stefanos Kachris3, Betty J Vogds2, Melissa DeRouen3, Alicia E Gitttleman3, Keith DeWyngaert3, Maria T Vlachaki41 Massachusetts General Hospital2 University of Oklahoma Health Sciences Center 3 New York University Medical Center4 Wayne State University

  16. STUDY DESIGN • Dosimetric comparison of IMRT versus 3DCRT in twenty patients with high-grade glioma. • Prescribed Dose: 59.4 Gy, 33 fractions, 4-10 MV • Dose constraints for brainstem: 55-60 Gy • Dose constraints for optic chiasm & nerves: 50-54 Gy • DVHs for target, brain, brainstem and optic nerves/chiasm were generated and compared • TCP and NTCP were also calculated and compared

  17. Brainstem p=0.023 p=0.003 p≤0.0001 p=0.006 p=0.01 50 p=0.004 40 30 IMRT Percent Organ Volume 3DCRT 20 10 0 p=0.06 p=0.047 % > 45Gy % > 54Gy p=0.01 p=0.059 p=0.047 p=0.015 p<0.0001 p≤0.0001 COMPARISON OF TARGET AND NORMAL TISSUE DOSIMETRY: IMRT v. 3DCRT p=0.004

  18. So, Can IMRT further reduce toxicities? • Almost no direct comparisons exist • Significantly improved DVHs can be achieved • These may be meaningful for sites such as the chiasm, pit gland, hypothalamus, hippocampus, etc. • Limited data support that cochlear sparing in the pediatric population might preserve hearing

  19. Compartmental Studies: Stem Cells • Subventricular zone stem cell compartment • Remains mitotically active in adulthood • Cells have self-renewal capacity • and differentiate into neurons or glia which • can migrate over long distances in the brain • and are involved in repair processes after brain injury/toxicity • In young rats, irradiation with 2 Gy produces apoptosis in the subependymal cell layer and also in the proliferating cellsin the hippocampus • which leads to prolonged impairment of repopulative capacity Doetsch, 1999; Hopewell, 1972; Bellinzona, 1996; Peissner, 1999; Tada, 1999

  20. The Role of the Hippocampus • Many patients exhibit learning/memory deficits with no pathologic changes, especially when the RT field involves the temporal lobes. • Recent work has shown that hippocampus-dependent learning and memory are strongly influenced by the activity of neural stem cells and their proliferative progeny. • The hippocampal granule cell layer undergoes continuous renewal and restructuring by the addition of new neurons. • Radiation at low doses affects the highly proliferative progenitors. A single low dose to the cranium of a mature rat is sufficient to ablate hippocampal neurogenesis. Monje ML: Radiation injury and neurogenesis. Current Opinion in Neurology. 16:129-34, 2003.

  21. Hippocampus Avoidance Hypothesis • The hippocampus plays a significant role in RT induced dementia • Doses as low as 2 Gy cause significant toxicity to the hippocampus • Conformal avoidance of the hippocampus may help reduce neurocognitive deficits

  22. Hippocampus Delineation by Software

  23. Hippocampus Avoidance with IMRT Avoidance Region 30 Gy 6 Gy 3 GY IMRT with tomotherapy achieves significant dose reduction (hippocampus), while delivering 30 Gy to the rest of the brain

  24. Can IGRT further reduce toxicities? • Even in the head, positioning is a significant issue • IGRT reveals this dramatically • Application of IGRT might permit more accurate dose delivery • H/N serves as a good surrogate for the brain in this regard

  25. Study Design • Twenty patients analyzed • 10 conventional patients • Prospectively enrolled • Daily measurements (6 degrees of freedom) with optically guided patient localization system • 10 IMRT patients • Plans analyzed and selected analysis of impact daily set-up variation

  26. Mean Set-up Error (SD) Mean Vector: 6.97 mm

  27. 6.97 mm shift- Optic Chiasm

  28. 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5 5 5 5 5 5 5 5 5 5 5 5 5 10 10 10 10 10 10 10 10 10 10 10 10 10 15 15 15 15 15 15 15 15 15 15 15 15 15 20 20 20 20 20 20 20 20 20 20 20 20 20 25 25 25 25 25 25 25 25 25 25 25 25 25 30 30 30 30 30 30 30 30 30 30 30 30 30 0 0 0 0 0 0 0 0 0 0 0 0 0 5 5 5 5 5 5 5 5 5 5 5 5 5 10 10 10 10 10 10 10 10 10 10 10 10 10 15 15 15 15 15 15 15 15 15 15 15 15 15 20 20 20 20 20 20 20 20 20 20 20 20 20 25 25 25 25 25 25 25 25 25 25 25 25 25 30 30 30 30 30 30 30 30 30 30 30 30 30 Treatment # Treatment # Treatment # Treatment # Treatment # Treatment # Treatment # Treatment # Treatment # Treatment # Treatment # Treatment # Treatment # Treatment Treatment Treatment Treatment Treatment Treatment Treatment # # # # # # # Treatment Treatment Treatment Treatment Treatment Treatment # # # # # # 1. Ideal 1. Ideal 1. Ideal 3. Median 3. Median 3. Median 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) Vector (mm) 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5 5 5 5 5 5 5 5 10 10 10 10 10 10 10 10 15 15 15 15 15 15 15 15 20 20 20 20 20 20 20 20 25 25 25 25 25 25 25 25 30 30 30 30 30 30 30 30 0 0 0 0 0 0 0 0 5 5 5 5 5 5 5 5 10 10 10 10 10 10 10 10 15 15 15 15 15 15 15 15 20 20 20 20 20 20 20 20 25 25 25 25 25 25 25 25 30 30 30 30 30 30 30 30 Treatment # Treatment # Treatment # Treatment # Treatment # Treatment # Treatment # Treatment # Treatment # Treatment # Treatment # Treatment # Treatment # Treatment # Treatment # Treatment # 2. Best 2. Best 4. Worst 4. Worst Paranasal Sinus – Daily Offset

  29. CNS Tumors with a role for Radiotherapy

  30. Roles of Radiotherapy • Post-op adjunct to: • decrease local failure • delay progression/relapse • prolong survival, eg GBM, AA • Primary curative therapy: • PNET, Germ Cell Tumors, Pilocytic astrocytoma • To halt tumor growth: • Meningioma, Schwannoma • To alter endocrine function • To palliate

  31. Radiotherapy Improves Survival

  32. Radiotherapy improves Local Control Craniopharyngioma as a case-study: 34 literature reports

  33. Radiotherapy diminishes Local Failure Meningioma as a case-study: Literature reports

  34. The Impact of Radiation Dose Medulloblastoma as a case-study: Literature reports Decreasing posterior fossa dose increases relapses

  35. The Impact of Radiation Dose Medulloblastoma as a case-study: Clinical Trials • 2 -ve Ph III trials • CCG 923: 36 (#44) vs. 23.4 (#45) Gy CSI. • 3 yr isolated neuraxis failure: 2/44 vs. 11/45. • SIOP II: 4 arms; 35 vs. 25 Gy CSI +/- pre-RT chemo • 5 yr RFS= 75 vs. 42% for chemo RT arms Decreasing CSI dose increases relapses

  36. 120 UCSF/Harvard: Implant 1. Dose escalation matters 2. Focal boost volumes can be identified 3. RT can be focally delivered 100 80 60 RTOG HFX Median Survival (Wks) RTOG 9803 (3D CRT) is exploring this range UCSF/Harvard: Control 40 Canada TID 20 BTCG, RTOG, ECOG No RT 0 0 20 40 60 80 100 120 Dose (Gy) GBM: Dose Escalation

  37. RTOG 9305: GBM RS Ph III trial • 203 patients with GBM • 60 Gy + BCNU +/- RS boost (15-24 Gy) • Median f/u 44 months • MS: 14.1 vs 13.7 months • 2 yr survival: 22 vs 18% • 3 yr survival: 16 vs 8% • General QOL & cognitive function comparable RADIOSURGERY NOT PROVEN TO PROLONG SURVIVAL IN GBM Souhami, ASTRO 2002

  38. Technologies for dose-escalation 5 field Fractionated Stereotactic Radiotherapy Technique Phase II RTOG trial: RTOG 0023

  39. RTOG 0023: Results Although overall survival was not improved, there was a trend toward improved survival with FSRT for patients with total resection FSRT MIGHT BENEFIT GROSS-TOTALLY RESECTED GBM Cardinale, Red J, 2006

  40. RTOG 9508 Phase III Single Brain Mets: Survival 100 RT + SRS (Median survival = 6.5 mo) RT alone (Median survival = 4.9 mo) 80 P=0.0470 60 Percent alive 40 20 0 0 6 12 18 24 Months SRS = stereotactic radiosurgery.

  41. A B Infiltrative Margins Mets GBM

  42. MRSI for Treatment Planning • 34 pts (22 G3, 12 G4) evaluated with MRI/MRSI • MRI contours:T2 for initial field; T1 for boost • MRSI: Multivoxel technique: CNI (Choline/NAA Index) • Results: MRSI would change fields • T2 estimated microscopic region 50% larger than MRSI • T2 missed MRSI abnormality in 88% of pts (upto 28 mm) • T1 suggested lesser volume than MRSI • T1 suggested different location than MRSI Pirzkall A: IJROBP 2001 McKnight: J Neurosurg, 2002: 90% sensitivity & 86% biopsy specificity for CNI >2.5

  43. Conclusions • Radiotherapy plays a major role in the management of most primary brain tumors • Local failure is still paramount • Failed strategies: limited dose escalation, neutrons, brachytherapy, Imidazoles & BUdR • Newer technologies may allow an improved therapeutic index

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