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Workshop on Advanced Technologies in Radiation Oncology

Workshop on Advanced Technologies in Radiation Oncology. Kian Ang. Based on data from:.

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Workshop on Advanced Technologies in Radiation Oncology

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  1. Workshop on Advanced Technologies in Radiation Oncology Kian Ang

  2. Based on data from: • major clinical trials employing ‘traditional’ conformal radiation therapy (drug A) for the treatment of H&N cancer, what was the PRINCIPAL dose-limiting toxicity that precluded giving adequate radiation doses to the cancer? • completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug B, is there any evidence that drug B decreased the principal dose-limiting toxicity? • completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug B, is there any evidence that drug B improved the patients’ survival? • completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug C, is there any evidence that drug C decreased the principal dose-limiting toxicity? • completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug C, is there any evidence that drug C improved the patients’ survival? • completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug D, is there any evidence that drug D decreased the principal dose-limiting toxicity? • completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug D, is there any evidence that drug D improved the patients’ survival? • completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug E, is there any evidence that drug E decreased the principal dose-limiting toxicity? • completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug E, is there any evidence that drug E improved the patients’ survival? Specific Assignment Regimen: A= 3-D CRT, B= SRT, C= IMRT, D= IGRT/Proton, E= Other particles

  3. Based on data from: • major clinical trials employing ‘traditional’ conformal radiation therapy (drug A) for the treatment of H&N cancer, what was the PRINCIPAL dose-limiting toxicity that precluded giving adequate radiation doses to the cancer? • completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug B, is there any evidence that drug B decreased the principal dose-limiting toxicity? • completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug B, is there any evidence that drug B improved the patients’ survival? • completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug C, is there any evidence that drug C decreased the principal dose-limiting toxicity? • completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug C, is there any evidence that drug C improved the patients’ survival/LR CONTROL? • completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug D, is there any evidence that drug D decreased the principal dose-limiting toxicity? • completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug D, is there any evidence that drug D improved the patients’ survival? • completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug E, is there any evidence that drug E decreased the principal dose-limiting toxicity? • completed or ongoing, single or multi-institutional, RANDOMIZED clinical trials comparing drug A versus drug E, is there any evidence that drug E improved the patients’ survival? Specific Assignment Regimen: A= 3-D CRT, B= SRT, C= IMRT, D= IGRT/Proton, E= Other particles

  4. Topic & Analogy Important to differentiate between: Drug X vs Drug Y? or Regimen A vs B of Drug X? (cisplatin for HNSCC: Firm evidence is for 100 mg/m2, q3W but common prescription is ~30 mg/m2, qW or 75 mg/m2, q3W or even carboplatin, qW – q3W)

  5. Type & StrategyExamples 1. “Tolerable” but Mucositis love to reduce Xerostomia 2. “Acceptable”, if Stenosis (esophagus) incidence is <5-10% Necrosis (bone or ST) 3. Avoid at all costNeural injury underdose tumorParalysis, blindness Principal Dose-Limiting ToxicityHead and Neck Carcinoma

  6. 65 USA 60 UK Germany France 55 Maximal Cord Dose (Gy) 50 45 40 35 25 30 35 40 45 50 55 Average Cord Dose (Gy) Spinal Cord Tolerance Survey Fowler et al., Radiot Oncol, 2000

  7. Generating Evidence for IMRT In general, randomized trial is considered the gold standard for changing practice standard • Does dose escalation improve outcome? • Experience with HFX in HNSCC (15%  dose):Yes, but the benefit is < RT + cisplatin • Challenge: competing with RT + novel agents • Does better tumor coverage improve outcome? • Difficult or impossible to conduct phase III trial • Does NT sparing decrease late toxicity? • May not need to conduct phase III trial

  8. Generating Evidence In some clinical settings, phase III trial is • not rational (potential harm) • not necessary (longitudinal control) • not feasible (variability in toxicity reporting & need large N to show a difference)

  9. Nasopharyngeal Carcinoma: T3N2c

  10. Phase III Trial: 3-D vs IMRT (A vs C)Not Rational – e.g., T3-4 NPC

  11. Ipsilateral RT for Tonsil Carcinoma

  12. Alternative to Randomized Trial? Reproduce (validate) single institution’s data preferably in multi-institutional setting

  13. IMRT for Oropharynx Cancer • 2000-June 2003: 133 patients • Age: 30-75 (53) years; 85% male • Site: tonsil-52%; tongue base-40% • T1-2(x): 114; T3-4: 19 • Chemotherapy: 28 (T3-4 or N2-3) • 3-Y local control: 95% • 3-Y overall survival: 93% Garden et al., 2005

  14. IMRT for Oropharyngeal SCCRTOG Protocol H-0022 (Eisbruch & Chao) Stage: T1-2 N-1 Site: Tonsil, BOT, Soft Palate R E G I S T E R Gross disease PTV: 66 Gy/30 FX Subclinical disease PTV: 54-60 Gy/30 FX Boost of 4-6 Gy/2-3 FX to the tumor PTV allowed

  15. RTOG 0022 – ASTRO 2006 • Study population: 67 patients (14 centers) • Tumor: tongue base-20 (39%), tonsil-33 (49%), soft palate 8 (12%) • Stage: T1-25%, T2-75%; N0-57%, N1-43% • Median follow-up: 1.6 (0.2-3.8) years • LR progression: 3 patients (4.9%) • No metastatic disease observed A Eisbruch, J Harris, A Garden, C Chao, W Straube, C Schultz, G Sanguineti, C Jones, W Bosch, K Ang

  16. IMRT ± Chemo for NPC (Single Institutions)

  17. IMRT for NPCRTOG Protocol H-0225 (Lee & Garden) IMRT: 2.12 Gy/F/d X 33 F to  95% of GTV 1.8 Gy/F/d X 33 F to  95% of CTV R E G I S T E R Stage: I-IVb Histology: WHO I-III Chemotherapy (T2b or N+) Concurrent: Cisplatin x 3 Adjuvant: Cisplatin + 5-FU

  18. Generating Evidence In some clinical settings, phase III trial is • not rational (potential harm) • not necessary (longitudinal control) • not feasible (variability in toxicity reporting & need large N to show a difference)

  19. 6 Mos 12 Mos Group N Mean Flow** N Wilcoxon Rank Sum 3DCRT* 12 0.33 11 0.43 p = 0.43 IMRT 38 0.49 20 0.82 p = 0.002 *Includes patients receiving 3DCRT fields with IMRT boost ** Relative to pretreatment flow: mean recovery rate of 4% per month from 6 to 12 months post-RT Recovery of Salivary Flow (A vs C) Mean Flow** Chao et al., Sem Radiat Oncol, 2002

  20. Recovery of Saliva Flow (A vs C) Kam et al., ASCO 2005 (NPC) Impact on QOL parameters was less obvious IMRT Non-IMRT p < 0.0001 0.0001 0.0001

  21. Patient with Tongue Base Carcinoma 19 CT Scans over 47 Days Elapsed Days Patient Immobilized with Acquaplast MaskCTs Aligned Using BBs on Mask Barker et al. IJROBP 59:960, 2004 & Lei Dong et al. (MDACC)

  22. Changes in Anatomy during Therapy Course Three Weeks into RT Planning CT Barker et al. IJROBP 59:960, 2004 & Lei Dong et al. (MDACC)

  23. Changes in Anatomy during Therapy Course Planning CT Mid Course CT Target Before RT Course Lei Dong et al. (MDACC)

  24. 26Gy Original Plan Four Weeks Later (Mapped back to the original planning CT using deformable registration) Dosimetric Impact of Anatomic Changes Barker et al. IJROBP 59:960, 2004 & Lei Dong et al. (MDACC)

  25. CTV1-2ndCT CTV1-plan CTV2-2ndCT CTV2-plan CTV3-2ndCT CTV3-plan L Parotid-2ndCT L Parotid-plan R Parotid-2ndCT R Parotid-plan cord-2ndCT cord-plan Right Parotid Dose: Planned vs Delivered CTV1 Cord CTV2 CTV3 R Parotid L Parotid Lei Dong et al. (MDACC)

  26. Generating Evidence In some clinical settings, phase III trial is • not rational (potential harm) • not necessary (longitudinal control) • not feasible (variability in toxicity reporting & need large N to show a difference)

  27. Toxicity Recording & Reporting JCO 22: 19, 2004

  28. Type of toxicityEvidence 1. “Tolerable” Have longitudinal& Xerostomiaphase III data on flow 2. “Acceptable”, if Difficult to generate <5-10% (necrosis) phase III data 3. Avoid at all costImpossible (unethical?) CNS injury to obtain phase III data Principal Dose-Limiting ToxicityHead and Neck Carcinoma

  29. Value of IGRT or Protons (D) Other Toxicity & Tumor Control Assess in defined patient subsets (phase III for NPC) Parotid dose 3-D CRT: >50 Gy IMRT: “~26 Gy” Clear in salivary flow Need to show clin benefit ! Will improve D-R data IGRT: ?? Gy Proton: ?? Gy

  30. Value of Other Particle Therapies (D) Exploiting potential advantages in: ? RBE ? Dose Distribution

  31. Resources for Clinical Research Training Quality Control

  32. Radiotherapy & Oncology 69: 227, 2003 http://www.rtog.org/hnatlas/main.html RP Level I Level II Level III Level V Level IV Level VI Training & QC: H&N Atlas

  33. Primary PTV Secondary PTV Organ at Risk Training & QC: IMRT Credentialing • Primary PTV 4 cm diameter 4 TLD • Secondary PTV 2 cm diameter 2 TLD • Organ at risk 1 cm diameter 2 TLD • Axial and sagittal radiochromic films 1º PTV treated to 6.6 Gy 2º PTV treated to 5.4 Gy OAR limited to < 4.5 Gy Courtesy: G. Ibbott Designed in collaboration with RTOG; Molineu et al, IJROBP, October 2005

  34. Phantom Results *34% of institutions failed on the first attempt Courtesy: G. Ibbott

  35. CTV56 CTV63 Protocol Training & QC Online Review CTV56 CTV63 Protocol ATC Advanced Technology Consortium

  36. Summary • IMRT (Regimen C) • It is an important progress for treatment of patients with H&N cancer • Requires training & QC to do it well • Firm data exist on xerostomia reduction • Need more multi-institutional trials to validate strong single institutional data on tumor control • IGRT, proton beam, & other particle therapies (Regimens D & E) • Need well designed studies to test & document their values in tumor control and toxicity reduction

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