1. Workshop on Advanced Technologies in Radiation Oncology Kian Ang

2. Specific Assignment Regimen: A= 3-D CRT, B= SRT, C= IMRT, D= IGRT/Proton, E= Other particles  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? Based on data from:

3. Specific Assignment  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? Based on data from: 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/m 2, q3W but common prescription is ~30 mg/m 2, qW or 75 mg/m 2, q3W or even carboplatin, qW – q3W)

5. Principal Dose-Limiting Toxicity Head and Neck Carcinoma Type & Strategy Examples 1. “Tolerable” butMucositis love to reduceXerostomia 2. “Acceptable”, ifStenosis (esophagus) incidence is <5-10% Necrosis (bone or ST) 3. Avoid at all cost Neural injury underdose tumorParalysis, blindness

6. Spinal Cord Tolerance Survey 35 40 45 50 55 60 65 25303540455055 USA UK Germany France Average Cord Dose (Gy) Maximal Cord Dose (Gy) Fowler et al., Radiot Oncol, 2000

7. Generating Evidence for IMRT  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 In general, randomized trial is considered the gold standard for changing practice standard

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 SCC RTOG Protocol H-0022 (Eisbruch & Chao) REGISTERREGISTER Stage: T1-2 N-1 Site: Tonsil, BOT, Soft Palate 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 A Eisbruch, J Harris, A Garden, C Chao, W Straube, C Schultz, G Sanguineti, C Jones, W Bosch, K Ang  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

16. IMRT ± Chemo for NPC (Single Institutions) Center NStage FU (mo) LC DM-Free Bucci IJROBP, 2004(abs) 118 50% T3-4 30 96% 72% (4-year data) Kam IJROBP, 2004 6351% T3-4 29 92% 79% (3-year data) Wolden IJROBP, 2005 74 51% T3-4 35 91% 78% (3-year data)

17. IMRT for NPC RTOG Protocol H-0225 (Lee & Garden) REGISTERREGISTER Stage: I-IVb Histology: WHO I-III 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 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. Recovery of Salivary Flow (A vs C) 20 11 p = 0.002 p = 0.43 38 12 0.49 0.33 IMRT 3DCRT* 0.82 0.43 N Wilcoxon Rank Sum N Mean Flow** Group *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 6 Mos 12 Mos Chao et al., Sem Radiat Oncol, 2002 Mean Flow**

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

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

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

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

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

25. Right Parotid Dose: Planned vs Delivered 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 R Parotid CTV1 CTV2 CTV3 Cord 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. Principal Dose-Limiting Toxicity Head and Neck Carcinoma Type of toxicity Evidence 1. “Tolerable”Have longitudinal & Xerostomia phase III data on flow 2. “Acceptable”, ifDifficult to generate <5-10% (necrosis)phase III data 3. Avoid at all cost Impossible (unethical?) CNS injuryto obtain phase III data

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

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

31. Resources for Clinical Research Training Quality Control

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

33. 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 Secondary PTV Primary PTV Organ at Risk Designed in collaboration with RTOG; Molineu et al, IJROBP, October 2005 Courtesy: G. Ibbott

34. Phantom Results *34% of institutions failed on the first attempt PhantomH&NProstateThoraxLiver Irradiations20549254 Pass12633142 Fail5143- Under analysis or at institution 16642 Unevaluable1264- Year introduced20012004 2005 Courtesy: G. Ibbott

35. Training & QC Online Review ATC Advanced Technology Consortium Protocol CTV 63 CTV 56 Protocol CTV 63 CTV 56

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