1. V. Budach – Statements on H&N Cancer - 1 Discussion Panel on Quality of Life and Radiotherapy in Head and Neck Cancer Volker Budach, MD, PhD Head Department for Radiation Oncology Charité Campus-Mitte Berlin Interdisciplinary Workshop on Modern Treatment Options Statements on Head and Neck Caner Frankfurt, 27-28 of January 2006

2. V. Budach – Statements on H&N Cancer - 2  Most of the studies addressing chemoradiation of locally advanced H&N cancer report increased acute and in some instances also late morbidities!  Is this a valid observation which can be supported by published literature results?  Are the data sufficient to address this question? Quality of Life Issues and Acute Toxicity/Late Morbidity Items in Chemoradiation of Locally Advanced Head and Neck Cancer

3. V. Budach – Statements on H&N Cancer - 3 Toxicity in random. head & neck trials: RT vs. RT-CHX (grade >=III) Concurrent RT-CHX (“older studies“) drug(s) %-diff. n end point reference BLM +54.0% * 199 acute Eschwege et al. 1987 BLM/MTX +50.0% * 96 acute Fu et al. 1987 MTX +9.0% * 313 acute Gupta et al. 1990 5-FU +11.7% * 282 acute Sanchiz et al. 1990 5-FU +20.5% * 175 acute Bowman et al. 1994 mean +23.7% 1065 acute 5-FU grade 4:+4.4% 136 late Collin et al. 1972 BLM/MTX +5.0% 96 late Fu et al. 1987 MTX “not enhanced“ 313 late Gupta et al. 1990 *= significantly more pat. with severe mucosa and/or skin toxicity W. Budach, personell communication

4. V. Budach – Statements on H&N Cancer - 4 Toxicity in random. head & neck. trials: RT vs. RT-CHX (Concurrent RT-CHX: grade >=III) drug(s) %-diff. n end point reference MMC (adj) +0.2% 113 acute Haffty et al. 1983 MMC -12.0% 117 acute Weissberg et al. 1989 P/5-FU +22.0% * 270 acute Wendt et al. 1998 P-P/5-F +9.2% 147 acute Al-Sarraf et al. 1998 P/5-FU +30.0% * 222 acute Calais et al. 1999 P (daily) +13.8% 130 acute Jeremic et al. 2000 mean +16.6% 999 acute MMC +2.0% 117 late Weissberg et al. 1989 P/5-FU +3.6% 270 late Wendt et al. 1998 P/5-FU +12.0% ** 222 late Calais et al. 1999 P (daily) +17.0% 130 late Jeremic et al. 2000 mean +8.2% 739 late *= significantly more pat. with severe mucosa and/or skin toxicity **= significantly more severe late toxicity W. Budach, personell communication

5. V. Budach – Statements on H&N Cancer - 5 Toxicity in random. head & neck. trials: RT vs. RT-CHX (Concurrent or alternating RT-CHX: grade >=III) Studies with 5-14% less RT-dose in CHX-arm RT dose end drug(s) with CHX %-diff. n point reference P/5-FUalt. -14% -2.5% 157 acute Merlano et al. 1991 P/5-FU -5% -2.0% 116 acute Brizel et al. 1998 MMC/5-FU -10% -9.5%* 384 acute Budach et al. 2000 mean -5.2% 774 acute P/5-FUalt. -14% -9.1% ** 157 late Merlano et al. 1991 P/5-FU -5% +2.0% 116 late Brizel et al. 1998 MMC/5-FU -10% -3.8% 384 late Budach et al. 2000 mean -3.1% 774 late *= significantly less pat. with severe mucosa toxicity **= significantly less severe late toxicity W. Budach, personell communication

6. V. Budach – Statements on H&N Cancer - 6 No Correlation between acute and late CHX excess toxicity (Evidence from 18 randomized clinical trials) NSCLC Head&Neck-Ca. Cervical-Ca. Rectal-Ca. R 2 = 0.074 -10 -5 0 5 10 15 20 -200204060 excess acute >=grade III toxicity [%] excess late >=gr. III toxcity [%] W. Budach, personell communication

7. V. Budach – Statements on H&N Cancer - 7 Developments in Safety, Toxicity and QOL Reporting in Oncology Clinical Trials Dimtrios Colevas MD Senior Investigator, Investigational Drug Branch, CTEP, National Cancer Institute Bethesda, MD ASTRO Education Session October 20,2005 Denver, Colorado Andy Trotti MD Director of Clinical Trials, Radiation Oncology H. Lee Moffitt Cancer Center Tampa, FL Deborah Watkins-Bruner RN PhD Director of Outcomes Research, Fox Chase Cancer Center Philadelphia, PA

8. V. Budach – Statements on H&N Cancer - 8 Presentations Evolution of Safety Reporting in Oncology Clinical Trials  Andy Trotti MD Use of the NCI-CTCAE Terminology and Grading System Use of QOL and Symptom Tools in Investigations of Adverse Effects  Debra Watkins- Bruner RN, PhD  Dimitri Colevas MD

9. V. Budach – Statements on H&N Cancer - 9 Provide background on how safety data is generated, analyzed and published. We will highlight areas in need of better methods, standards and guidelines in patient screening/data collection, data analysis, presentation, publication, and interpretation. Target audience: Primarily directed at the investigator (or the practitioner with a keen interest in toxicity/QOL) who wants to have a deeper understanding of toxicity profiles and QOL outcomes. Highlight opportunities for research questions. Objectives Research opportunity…

10. V. Budach – Statements on H&N Cancer - 10 Understand the strengths and limitations of the current toxicity reporting process for multimodality clinical trials Understand changes in the new NCI-Common Terminology Criteria system for adverse events (CTCAE) Understand the role of QOL and symptom tools in specific investigations of adverse effects Educational Objectives

11. V. Budach – Statements on H&N Cancer - 11 References and Sources Adverse Effects of Cancer Treatment: Metrics, Management and Investigations Seminars Radiation Oncology Volume 13, No 3, July 2003 Andy Trotti MD Director of Clinical Trials, Radiation Oncology H. Lee Moffitt Cancer Center Tampa, FL

12. V. Budach – Statements on H&N Cancer - 12 Evolution of Safety Reporting in Oncology Clinical Trials ASTRO Education Session October 20,2005 Denver, Colorado Andy Trotti MD Director of Clinical Trials, Radiation Oncology H. Lee Moffitt Cancer Center Tampa, FL

13. V. Budach – Statements on H&N Cancer - 13 Radiation Oncologist, H. Lee Moffitt Cancer Center Adverse Events: Assessment, Reporting and Interventions H&N Cancer Clinical Trials RTOG representative to NCI-CTC Revision Committees Ongoing initiatives to improve safety reporting Andy Trotti MD Background and Interests

14. V. Budach – Statements on H&N Cancer - 14 Grant funding: NCI, RTOG Intellectual Property Interest: “Safety Profiler” software to facilitate toxicity data collection and reporting. (NCI Small Business Grant to CTIS Informatics Inc, Rockville, MD) Disclosures A. Trotti

15. V. Budach – Statements on H&N Cancer - 15 How should we evaluate the adverse effects of cancer treatment on health status in oncology?

16. V. Budach – Statements on H&N Cancer - 16 Patient Relevance Specificity * Bentzen et al (Sem Rad Onc July 03) Adverse Effects Domains* A NALYTIC (Lab) SYMPTOMS OBJECTIVE (Exam) QUALITY OF LIFE & PATIENT REPORTED OUTCOMES Common Toxicity Criteria Research opportunity: Develop and use PROs to improve quality of symptom capture.

17. V. Budach – Statements on H&N Cancer - 17 QOL and symptoms scales are wholly subjective metrics--a highly individual personal perception. QOL scores are affected by one’s ability to cope/adapt to adversity QOL scores are influenced by cancer status QOL correlates with toxicity in some studies, not in others QOL may include diverse domains of social support, spirituality QOL = Toxicity QOL (assessed by patients) may be complimentary to, and may help to inform the clinician about adverse effects, but is not a substitute for adverse event reporting (as assessed by clinicians).

18. V. Budach – Statements on H&N Cancer - 18 Toxicity Efficacy How Do We Evaluate Therapeutic Gain? “What is the toxicity “price-tag”? “Is it worth it?”

19. V. Budach – Statements on H&N Cancer - 19 Toxicity Profile: RTOG 91-11 Larynx Preservation Trial Incidence Grade 3-4 Effects (%) Hematologic Infection Mucosal Pharyngeal Laryngeal Skin N & V Renal or GU Neurologic Other Concurrent Chemo-RT RT Alone Induction phase RT phase Induction Chemo 52 5 20 - 14 2 4 16 15 1 24 19 13 10 0 1 0 12 47 4 43 35 18 7 20 4 5 40 3 1 24 19 16 9 0 6

20. V. Budach – Statements on H&N Cancer - 20  CTC terms and reporting methods have been used for last 25 years.  Widely accepted as a the best reflection of “safety”.  Became a uniform multi-modality language in 2003 (CTCAE). New CTC promises to be more specific and information rich. Strengths CTC and Safety Reporting in Oncology

21. V. Budach – Statements on H&N Cancer - 21 Limitations  There are no guidelines or uniform methods for the capture, analysis, presentation and interpretation of safety data. It is may be interpreted differently by different modality specialists.  CTC data is a collection of secondary endpoints used to generate an overall picture or general safety profile of a given treatment program, to pick up gross trends and differences between arms/groups/studies. Analysis of selected injuries may also be informative.  We lack a common method to objectively and concisely summarize and communicate OVERALL toxicity burden. CTC and Safety Reporting in Oncology

22. V. Budach – Statements on H&N Cancer - 22 Limitations The incidence of a specific injury/symptom is often gleaned from small numbers of events. Evaluation of individual injuries should be interpreted with caution. Therapeutic studies are not powered to compare low rates of individual events. Most CTC scales (especially symptom scales) have not be validated for inter-rater reliability. Individual terms/scales were not designed to be used as “primary” endpoints (e.g., in specific toxicity analysis or intervention studies). CTC and Safety Reporting in Oncology

23. V. Budach – Statements on H&N Cancer - 23 Efficacy Concise Outcome Metrics Tumor response Survival Local Control Organ Preservation Summary Metrics “Toxicity profiles” >4000 identifiable and discreet forms of injury; a wide spectrum of variables; usually not binary. Prognostic Groups (AJCC Stage) Current toxicity metrics are data rich, but reporting practices vary widely and data are often in non-uniform format; usually cumbersome, difficult to summarize, interpret, compare and communicate How Do We Evaluate the Therapeutic Ratio? Safety Often simple binary outcomes

24. V. Budach – Statements on H&N Cancer - 24 Safety Efficacy Balancing Risk and Benefit This gap constrains our ability to make informed judgments about the balance of risks and benefits. Well develop endpoints and reporting methods Underdeveloped and lacking standards…

25. V. Budach – Statements on H&N Cancer - 25 “Toxicity profile” Data verification (audits; monitoring) The Safety Reporting Process in Oncology Schedule of required evaluations Evaluation/Screening (interview + exam + testing) Clinical documentation Assign toxicity terms and grades (coding) Data display and analysis Scientific Publication Data submission (CRFs/sponsor) Terminology and Grading System SAE/AE determination & reporting Adapted from Gwede, JOM 2002

26. V. Budach – Statements on H&N Cancer - 26 Schedule of required evaluations Evaluation/Screening (interview + exam + testing) Clinical documentation Interpret and apply a grade (coding) Data display and analysis Scientific Publication Data submission (CRFs/sponsor) “Toxicity profile” Terminology and Grading Criteria Data verification (audits; monitoring) SAE/AE determination & reporting Data Generation Data Submission/Analysis The Safety Reporting Process in Oncology Variations in data collection practices Variations in grading systems (# terms; acute/late; modalities) Variations in reporting methods Lack of standard summary methods “Deficiencies in the safety reporting process may lead to under-reporting and bias” Gwede (2002)

27. V. Budach – Statements on H&N Cancer - 27 Schedule of required evaluations Evaluation/Screening (interview + exam + testing) Clinical documentation Interpret and apply a grade (coding) Data display and analysis Scientific Publication Data submission (CRFs/sponsor) “Toxicity profile” Grading Criteria Data verification (audits; monitoring) SAE/AE determination & reporting Data Generation Data Submission/Analysis 4 Initiatives to Improve Safety Reporting Safety Profiler Electronic data capture and reporting tools CTCAE v 3.0 Wide Adoption of Uniform Terminology and Grading TAME Treatment Risk Classification System AERO (Safety Endpoint Data Collection & Reporting Standards) Adverse Events Reporting in Oncology

28. V. Budach – Statements on H&N Cancer - 28 Common Understanding of Toxicity Burden Common Data Collection, Display & Analysis Common Methods of Data Capture Common Terminology And Grading 4 Initiatives to Improve Safety Reporting…. Safety Profiler Electronic reporting methods & tools AERO Adverse Events Reporting in Oncology (Endpoint collection, Analysis & Reporting Standards) TAME Treatment Risk Classification System CTCAE v 3.0 Wide Adoption of Uniform Grading System

29. V. Budach – Statements on H&N Cancer - 29 Development and Widespread Adoption of the NCI-CTC (Common Toxicity Criteria) Initiative #1

30. V. Budach – Statements on H&N Cancer - 30 Why is toxicity terminology and grading important? Toxicity grading is only done in oncology, and not other medical specialties. Non-oncology trials use purely descriptive terminology (MEDRA language) and generally handle low incidence and low grade events. A great number of adverse events are generated during cancer treatment. Special terminology and grading facilitates recognition and management.

31. V. Budach – Statements on H&N Cancer - 31 Why is a uniform toxicity terminology and grading system important? Recognition of the injury Common language for communication Common severity “scaling” Drives interventions Data for toxicity/safety profiles

32. V. Budach – Statements on H&N Cancer - 32 The Evolution of Adverse Events Grading Systems System# Terms #Organs Modality Phase WHO (1979) 28 9 ChemoAcute CTC (1984) 48 13 ChemoAcute RTOG-A (1984) 14 13 RT Acute RTOG-L (1984) 16 13 RT Late SOMA (1995) 152 22 RT Late CTC v 2.0 (1998) 260 24 All*Acute CTCAE v 3.0 (2003) 1058* All All Acute & Late “The first comprehensive grading system for all modalities.”

33. V. Budach – Statements on H&N Cancer - 33 ctep.info.nih.gov/CTC3/ctc.htm A comprehensive terminology and grading system for acute and late effects for all modalities, for use in NCI supported clinical trials. NCI-CTCAE Common Toxicity Criteria for Adverse Events 2003 Terminology

34. V. Budach – Statements on H&N Cancer - 34 CTC Grading General guidelines 1 2 3 4 Mild Asymptomatic; No intervention indicated Moderate Symptomatic; interventions such as local treatment or meds may be indicated; Some interfere with function, but no impact on ADLs. Severe Very undesirable; multiple, disruptive symptoms; more serious interventions, including surgery or hospitalization may be indicated. Life threatening life threatening, catastrophic, disabling, or result in loss of organ, organ function, or limb High grade Low grade

35. V. Budach – Statements on H&N Cancer - 35 Discussion/questions…

36. V. Budach – Statements on H&N Cancer - 36 DEVELOPMENT OF ELECTRONIC DATA COLLECTION METHODS “Safety Profiler” Software Tools Initiative #2

37. V. Budach – Statements on H&N Cancer - 37 Electronic tools to facilitate clinical assessment, grading, and submission of adverse events data in clinical trials “SAFETY PROFILER” Tools Developed under a small business grant for NCI-CTEP

38. V. Budach – Statements on H&N Cancer - 38 Thank you

39. V. Budach – Statements on H&N Cancer - 39 Schedule of required evaluations Evaluation/Screening (interview + exam + testing) Clinical documentation Interpret and apply a grade (coding) Data display and analysis Scientific Publication Data submission (CRFs/sponsor) “Toxicity profile” Grading Criteria Data verification (audits; monitoring) SAE/AE determination & reporting Data Generation Data Submission/Analysis The Safety Reporting Process in Oncology Safety Profiler Tools address: Variations in data collection practices Access to CTC terms/grading language “Directed” vs “passive” screening Disease/protocol specific checklists Research opportunity: Develop disease-specific CTCAE templates (subsets) to facilitate the uniform capture of disease & protocol-specific AEs. Compare “passive” AE capture to “directed”AE capture.

40. V. Budach – Statements on H&N Cancer - 40 DEVELOPMENT OF SAFETY ENDPOINT DATA COLLECTION AND PUBLICATION STANDARDS Initiative #3 AERO Working Group Adverse Events Reporting in Oncology

41. V. Budach – Statements on H&N Cancer - 41 Only 51% reports addressed treatment related mortality Effects of surgery addressed in only 5/11 (45%) of surgery trials Late organ function: only 3% addressed feeding tube dependence; only 7% discussed tracheostomy dependence. Wide variations in grading systems and reporting methods Systematic Review of Variations in Safety Reporting In Phase III H&N Trials (1990-2003) Only 47% reported on late events 53 papers identified and reviewed from 41 trials Gwede/Trotti ASTRO 2005 Abs # 2208

42. V. Budach – Statements on H&N Cancer - 42 The lack of uniform data collection and reporting standards contributes to: Significant under-reporting of the scope and magnitude of both acute and late events Difficulty in interpreting safety data Difficulty in comparing safety data between trials Gwede/Trotti ASTRO 2005 Abs # 2208 Systematic Review of Variations in Safety Reporting In Phase III H&N Trials (1990-2003) Research opportunity: Conduct systematic review of variations in adverse event reporting in selected disease sites.

43. V. Budach – Statements on H&N Cancer - 43 The Need for Adverse Effects Reporting Standards in Oncology Trotti & Bentzen Journal of Clinical Oncology: 22 (1) January 2004 Adverse Events Reporting in Oncology (AERO Committee)

44. V. Budach – Statements on H&N Cancer - 44 AERO-H&N Working Group Rochester NY, April, 2004 Soren Bentzen (Chair) Andy Trotti (Co-Chair) Volker Budach (EORTC/DEGRO) A. Dimitrios Colevas (NCI/CTEP) David Pfister (MSKCC) Barbara Murphy (ECOG) Ann Setser (NCI/CTEP) Susan Davidson (Christie NHS Trust) Howard Fingert (Pfizer) Jay Cooper (RTOG) Jens Overgaard (DAHANCA) Drew Ridge (RTOG/ECOG/ACOSOG) Tom Pajak (RTOG) Ozlem Ataman (ESTRO-REACT) Brian O’Sullivan (NCIC/ACOSOG/CARO) Stanley Dische (ESTRO) MichelleSaunders (ESTRO) Kian Ang (RTOG) Arlene Forastiere (ECOG/RTOG) Gareth Griffith (MRC) Clement Gwede (RTOG/Moffitt) Cai Grau (DAHANCA) Stephen Edge (AJCC/ACOSOG) John Ioannides (CONSORT) 25 members; 13 organis.; 7 countries; 6 coop groups; 17 MDs (10 rad onc; 5 med onc; 2 surg); 3 stat; 2 NCI; 1 Industry; 2 clin. scient. Mahmut Oszahin (EORTC)

45. V. Budach – Statements on H&N Cancer - 45 1)Protocol Development Safety Endpoint Data Collection Guidelines 2) AERO Safety Reporting Standards (for scientific end-results and publications) AERO-H&N Committee Committee Aims:

46. V. Budach – Statements on H&N Cancer - 46 CTCAE v3.0 Multimodality H&N Criteria Bone marrow Diarrhea Fatigue Febrile neutropenia Hearing Infection Lab/metabolic Mucositis Neuropathy N&V Otitis Renal function Tinnitus Weight loss Airway obstruction Bone necrosis Dental loss Fibrosis Larynx dysfunction Lymphedema Neuropathy Skin atrophy Soft tissue necrosis Stricture (tube dependence) Taste alteration Thryoid function Trismus Voice and speech Xerostomia Cranial nerve injury Fistula Flap failure Hemorrhage Larynx dysfunction Lymphatics Perforation Shoulder dysfunction Speech Stricture Swallowing dysfunction Trismus Vascular injury Wound complication Wound infection Acute toxicity Late effectsSurgical effects Needed: standardized templates for collection of acute and late effects

47. V. Budach – Statements on H&N Cancer - 47 Safety Endpoint Data Collection RTOG 0522 (Plat/RT +/- erbitux) New safety section on drug rash grading and management Baseline: dysphagia During treatment to 8 weeks f/u: dysphagia, mucositis, larynx/edema (trach), radiation dermatitis Protocol specific: drug (erbitux rash) Follow-up (> 3 mo): dysphagia, FT use, larynx/trach, neuropath (sens & pain), hearing, fibrosis, mucosal necrosis, osteonecrosis. Other AEs (not listed) reported via routine AE guidelines (eg, SAEs). Research opportunity: Develop disease-specific CTCAE templates (subsets) to facilitate the uniform capture of disease & protocol-specific AEs. Compare “passive” AE capture to “directed”AE capture.

48. V. Budach – Statements on H&N Cancer - 48 RTOG 0234 and 0522: EGFR Inhibitor Rash Moderate Macular or papular Eruption or erythema With pruritus or other Associated symptoms; Localized desquamation Or other lesions covering <50% of body surface Area (BSA) Severe Severe, generalized Erythroderma or Macular, papular or Vesicular eruption; Desquamation Covering>50% BSA

49. V. Budach – Statements on H&N Cancer - 49 TAME Initiative #4 Development of a concise adverse event summary and treatment risk classification system

50. V. Budach – Statements on H&N Cancer - 50 TAME: Dimensions of Risk in Oncology Dimension Short Term Long Term Mortality from treatment How “TAME” is this treatment? “T” (Toxicity, acute) “A” (Adverse late effects) “M” (Mortality) End Results Reporting “E” (End-Results) Proposed Reporting System

51. V. Budach – Statements on H&N Cancer - 51 Thank you Acute Toxicity (Safety) Profile: RTOG 90-03 “Worst grade” summary: STD HFX AF-S AF-C Gr 1-2: 63% 42% 36% 40% Gr 3-4: 35% 56% 51% 59%

52. V. Budach – Statements on H&N Cancer - 52 “Worst Grade Summary Method” Used by RTOG >25 years Exact origin of the algorithm unknown Summarizes AE profile data by consolidating (and reducing) the number of events within and among organ systems, and across time WGSM: COUNTS ONLY ONE EVENT PER PATIENT Ignores “multiplicity”: multiple events in the same patient

53. V. Budach – Statements on H&N Cancer - 53 Does the “Worst Grade Summary Method” (WGSM) represent toxicity among different trials in a consistent and unbiased way?

54. V. Budach – Statements on H&N Cancer - 54 Thank you CALCULATING THE Grade 3-4 WORST GRADE INCIDENCE: RTOG 90-03 # Gr 3-4 events UTILIZED for the calculation= 94 (35%) # Gr 3-4 events COLLECTED within and across categories = 140 DIFFERENCE: 140 - 94 = 46 46/140 (33%) OF EVENTS “EXCLUDED” FROM THE WGSM CALCULATION

55. V. Budach – Statements on H&N Cancer - 55 Thank you High Grade Toxicity Burden Excluded by RTOG WGSM in 5 H&N Trials: 90-03, 91-11, 95-01, 97-03, 99-14 ** UTILIZED=used to calculate WGSM incidence ** COLLECTED= # Gr 3-4 events COLLECTED within and across categories ….30-70% of high-grade events are excluded using the worst grade summary method.

56. V. Budach – Statements on H&N Cancer - 56 Summary Reporting Methods Worst Grade Summary Method (WGSM ) Did the patient experience at least one high grade (e.g., grade 3+) toxicity? T-score How many high grade toxicities did the patient experience?

57. V. Budach – Statements on H&N Cancer - 57 # high grade events in a patient cohort # patients in a patient cohort T-Score includes all acute CTC (and/or RTOG) grade 3-4 events for all toxicity items measured. T-Score = “T-Score” (Acute Toxicity)

58. V. Budach – Statements on H&N Cancer - 58 Thank you T Scores (include ALL Gr 3-4 events) in 5 RTOG H&N Trials >5 fold (500%) difference in toxicity burden across programs “T-score uses ALL events and corrects for multiplicity”

59. V. Budach – Statements on H&N Cancer - 59 Thank you Increasing Toxicity in RTOG H&N Trials T-Score (ALL events): 500% increase in high grade toxicity Worst grade summary method: 200% increase in high grade toxicity Systematic bias: high toxicity programs appear less toxic Relative difference Reporting GAP= 300%

60. V. Budach – Statements on H&N Cancer - 60 Hypothetical Toxicity Burden “Risk Classes”* Severity Class T-score Range I Low Burden II Moderate Burden III High Burden IV Extreme Burden *For Advanced (AJCC III-IV) H&N Cancer < 0.6 0.7-1.0 1.1-2.4 > 2.5 Treatment Options I 95-01(RT), 90-03(RT II 90-03 (CB-RT), 91-11 (RT), 90-03 (HFX), 90-03 (SC) III 91-11(RT/CT), 97-03 (CT/RT), 99-14 (RT/CT), 91-11(CT/RT), 95-01 (RT/CT) IV 97-03 (RT/CT), 97-03 (RT/CT)

61. V. Budach – Statements on H&N Cancer - 61 Toxicity Profile: RTOG 91-11 Larynx Preservation Trial Incidence Grade 3-4 Effects (%) Hematologic Infection Mucosal Pharyngeal Laryngeal Skin N & V Renal or GU Neurologic Other Concurrent Chemo-RT RT Alone Induction phase RT phase Induction Chemo 52 5 20 - 14 2 4 16 15 1 24 19 13 10 0 1 0 12 47 4 43 35 18 7 20 4 5 40 3 1 24 19 16 9 0 6

62. V. Budach – Statements on H&N Cancer - 62 TAME reporting in RTOG 91-11 TAM RT alone0.770.593% Induction CT/RT 2.160.435% Concurrent CT-RT 1.970.483% “Approximately 2.5 TIMES more acute toxicity burden with chemotherapy”

63. V. Budach – Statements on H&N Cancer - 63 A concise method of quantifying the toxicity experience which consistently reflects (approximates) toxicity burden. TAME A supplement (not a substitute) for traditional reporting methods (toxicity profiles). Requires no new instruments or tools. Would probably benefit from more uniform methods of data collection. Reflects all 4 dimensions of toxicity burden (scope, severity, time, and multiplicity) Research opportunity: Application of TAME reporting system to additional disease sites and research databases from different research organizations.

64. V. Budach – Statements on H&N Cancer - 64 Toxicity Profile: RTOG 91-11 Larynx Preservation Trial Incidence Grade 3-4 Effects (%) Hematologic Infection Mucosal Pharyngeal Laryngeal Skin N & V Renal or GU Neurologic Other Concurrent Chemo-RT RT Alone Induction phase RT phase Induction Chemo 52 5 20 - 14 2 4 16 15 1 24 19 13 10 0 1 0 12 47 4 43 35 18 7 20 4 5 40 3 1 24 19 16 9 0 6 Research opportunity: Identify and validate CTC “clusters” that the most “clinically important” to facilitate the interpretation of CTC data.

65. V. Budach – Statements on H&N Cancer - 65 Summary The current safety reporting process has strengths and limitations. The “new” CTC system (CTCAE) is more specific and comprehensive, promising to provide more information rich data. Current deficiencies may result in systematic under- reporting of toxicity. Additional guidance and standards are needed to improve the reliability and utility of safety data.

66. V. Budach – Statements on H&N Cancer - 66 Summary Lack of a unbiased and concise standard toxicity summary method constrains our ability to objectively compare safety among treatment options Ongoing initiatives to improve the generation and use of CTC data promises make safety reporting more accurate, reliable and useful.

67. V. Budach – Statements on H&N Cancer - 67 Thank you

68. V. Budach – Statements on H&N Cancer - 68 Terminology and Jargon Tissue injury and symptoms may occur from any form of treatment Tissue injury jargon: morbidity, complications, toxicity, side effects, reactions, late effects. Safety vs Risk Clinical Trials Preferred Term: “ADVERSE EVENTS” Adverse Events may or may not be related to Rx. Adverse Effects are designated as related on data review.

69. V. Budach – Statements on H&N Cancer - 69 CTC Grading General guidelines 1 2 3 4 Mild Asymptomatic; No intervention indicated Moderate Symptomatic; interventions such as local treatment or meds may be indicated; Some interfere with function, but no impact on ADLs. Severe Very undesirable; multiple, disruptive symptoms; more serious interventions, including surgery or hospitalization may be indicated. Life threatening life threatening, catastrophic, disabling, or result in loss of organ, organ function, or limb High grade Low grade

70. V. Budach – Statements on H&N Cancer - 70 Why is a common language important?

71. V. Budach – Statements on H&N Cancer - 71 Contains four fundamental dimensions: >SCOPE: variety of effects >SEVERITY: grade >MULTIPLICITY: multiple events coincident in the same patient >TIME: duration, or recurring pattern Defining “Toxicity Burden” “The aggregate combination of short and long-term high-grade adverse effects (events) on health status occurring during treatment or in follow-up.” Captured and reported by CTC Captured but NOT reported

72. V. Budach – Statements on H&N Cancer - 72 Acknowledgements EXTERNAL ADVISORY PANEL Mary Gospodarowicz Brian O’Sullivan Stephen Edge Jay Cooper Dimitri Colevas Tom Pajak Søren M. Bentzen Norman Coleman Drew Ridge Arlene Forastiere COLLABORATIONS Tom Pajak (RTOG) Rebecca Paulus (RTOG) Jonathan Harris (RTOG) MOFFITT TEAM Clement Gwede Paul Jacobsen Tom Sellers Ben Djulbegovic Martine Extermann Craig Beam Satya Saranga

73. V. Budach – Statements on H&N Cancer - 73 Design of the ARO 95-6 Study HART (77.6 Gy/6 wks.) (77.6 Gy/6 wks.) Stages III/IV*R C-HART + MMC/5-FU (70.6 Gy/6 wks.) * Locally advanced H&N-cancer of the oral cavity, oro- and hypopharynx stratified according to centres, tumor sites, N-stage and grading

74. V. Budach – Statements on H&N Cancer - 74 T2 1 21527 T3 51546369 T4 141720744282 T1 336 Total Stage III:5.5%(n=21) Stage IV:94.5%(n=363) N0 Total N1N2N3 TNM-Matrix 1933 27755384 Multicentric Phase-III Trial “Accelerated Hyperfractionation ± 5-Fluorouracil / Mitomycin C for locally advanced head & neck cancer (ARO 95-6)

75. V. Budach – Statements on H&N Cancer - 75 ARO 95-06

76. V. Budach – Statements on H&N Cancer - 76 ARO 95-06

77. V. Budach – Statements on H&N Cancer - 77 ARO 95-06 Acute Toxicity (EORTC / RTOG) (n = 348) Erythema Epithelio-Pigmen-MucositisDysphagia XerostomiaDysgeusia lysis tation p=0.30** p=0.24*** p=0.30 p=0.65 p=0.82 p=0.60 p=0.98 Brunner*p=0.30** p=0.24*** p=0.30 p=0.65 p=0.82 p=0.60 p=0.98 14.08.2001 *non-parametric analysis of variance for repeated measures **isolated significance at 5 th and 6 th time points (Mann-Whitney-U-test) ***isolated significance at 6 th time point (Mann-Whitney-U-test)

78. V. Budach – Statements on H&N Cancer - 78 Late Morbidity (EORTC/RTOG) (n=331) Brunner* Xero-**Dys-Dys-*** Tele-FibrosisTrismusPlexo-Osteorad.Pigmen-Lymph- Mucosal Neurol. analysis stomiageusiaphagiaangiect.pathynecrosistationedema necrosis sympt. @ 5 yrs.p=0.58p=0.79p=0.24p=0.43p=0.95p=0.82p=0.29 p=0.96p=0.74p=0.75 p=0.26 p=0.93 19.06.2003 *non-parametric analysis of variance for repeated measures **isolated significance at 11 th observation (Mann-Whitney-U-test) ***isolated significance at 2 nd, 3 th, 5 th and 9 th observation (Mann-Whitney-U-test)

79. V. Budach – Statements on H&N Cancer - 79 Months from Entry ARO 95-06

80. V. Budach – Statements on H&N Cancer - 80 Months from Entry ARO 95-06

81. V. Budach – Statements on H&N Cancer - 81 Months from Entry ARO 95-06

82. V. Budach – Statements on H&N Cancer - 82 Months from Entry ARO 95-06

83. V. Budach – Statements on H&N Cancer - 83  How to improve the therapeutic ratio by optimizing the risk – benefit ratio?  Do we have to address an improvement of the treatment results at the same level of toxicities and morbidities?  How closely are quality of life measures related to acute and late radiation effects? Open Questions for the design of clinical trials in Locally Advanced Head and Neck Cancer involving chemoradiation