1. Surgery as a Contemporary Therapeutic Modality for Head and Neck Cancer Southern Ohio Medical Center Grand Rounds May 16, 2008 David E. Schuller, M.D. Vice President, Medical Center Expansion and Outreach Professor, Department of Otolaryngology – Head and Neck Surgery John W. Wolfe Chair in Cancer Research CEO Emeritus, The James Director Emeritus, Comprehensive Cancer Center

6. Master Plan - 2016

7. Cancer in Ohio Cancer is the #1 killer in Ohio 10 th highest rate in US for cancer deaths for women 13 th highest rate in US for cancer deaths for men 6 th highest death rate for breast cancer 6 th highest death rate for colorectal cancer Every hour of every day, 7 people in Ohio are diagnosed with cancer Every hour of every day, 3 people in Ohio die from cancer

8. Cancer in Ohio Based on American Cancer Society estimates, medical expenditures for cancer cases diagnosed in Ohio annually exceed $1 billion; furthermore, total annual costs, including lost productivity, exceed $8 billion. Source: Ohio Cancer Incidence Surveillance System Status Report, 2003, Ohio Department of Health, April 2004

9. Cancer in Ohio 2010 Ohio’s population is aging Source: U.S. Census Bureau, March 2005

10. Source: Ohio Department of Health Data 2004, U.S. Census Bureau 2004, KSA Analysis 2001 Number of Cancer Cases Cancer Incidence Number of cancer cases Cancer Incidence Rate / 100,000 2001 Ohio Cancer Cases and Incidence Cancer in Ohio Cancer incidence increases as the population ages

11. OSU Comprehensive Cancer Center NCI designated “Comprehensive” since 1976 One of only 39 comprehensive cancer centers in the USA Only 1 of 5 cancer centers in nation with special NCI Phase I and Phase II contracts for clinical trials 250 cancer investigators in 15 of the 19 colleges Generates, on average, more than $100M annually in cancer-relevant research funding The OSU Cancer Program

12. James Cancer Hospital and Solove Research Institute Research teaching hospital training the doctors of tomorrow Only free-standing cancer hospital in Ohio One of only 10 hospitals exempt from Medicare Prospective Payment System (PPS) Founding member of National Comprehensive Cancer Network (NCCN) The OSU Cancer Program

13. Background Information Therapeutic Options 1.Surgery – locoregional 2.Radiotherapy – locoregional 3.Chemotherapy – Systemic 4.Chemoradiotherapy – locoregional

14. Background Head and Neck Cancer Survival ImprovementNO Failure Site* Local/Regional23% Distant18% *Laramore, et al., Int. J. Rad. Onc. Biol. Phys., 23(4), 1992

15. Background Head and Neck Cancer Quality of Life Improvement Probably Patient Compliance Major Challenge (36%)* *Laramore, et al., Int. J. Rad. Onc. Biol. Phys., 23(4), 1992

18. Definition of Terms Phase I Trial - Toxicity Recurrent/metastatic, any type/site Phase II Trial - Response Recurrent/metastatic, type/site specific Phase III Trial - Survival Previously untreated, controlled, randomized

19. Research Capabilities Single Institutions Pilot Studies Individual Cooperative GroupPhase I/II Trials Multiple Cooperative Groups (HNI) Phase III Trials

20. Treatment Modalities Surgery Radiation Therapy Chemotherapy Chemoradiotherapy... Non-specific “bigger is better”

21. Tx Modalities in New Millennium Surgery organ preservation/ reconstructive techniques Radiation Therapy conformal, intraoperative, intensity modulated Chemotherapy molecular targeted therapies... specific and focused

22. Advanced Stage Head & Neck Cancer Conventional therapy (S + RT) 38% 4 yr survival* Improved locoregional control failure at distant sites Patient non-compliance compromises ability to improve survival rates *Kramer et al, Head and Neck Surg. 1987

23. Head and Neck Intergroup Study 0034* Phase III Trial – Surgery + RT vs. Surgery + sequential CT/RT No survival improvement Decreased distant metastases – 15% vs. 23% (p = 0.03) High failure rates – local 15.3% – regional 9.5% – distant 14.9% * Laramore, et al., Int J Radiat Oncol Biol Phys., 1992

24. Problems High rate of disease recurrence No survival advantage with addition of chemotherapy Poor patient compliance –Head and Neck Intergroup Study 0034 * only 42% completed all treatment on experimental arm patient refusal - most common reason *Laramore, et al., Int J Radiat Oncol Biol Phys., 1992

25. Goals of Intensification Regimen Intensify treatment to primary tumor, neck nodes and distant sites Improve patient compliance Assess toxicity related to therapy

26. Intensification Schema Eligibility – previously untreated, resectable SCC of oral cavity, oropharynx or hypopharynx – Clinical Stage III or IV ( or Stage II of hypopharynx) – Karnofsky Performance Status > 60 Preop: accelerated, fractionated chemoradiotherapy Surgical resection + intraoperative RT (IORT) Postop: concurrent chemoradiotherapy

27. IORT Directly visualized boost to area of surgical margins – Greatest benefit to negative or microscopically positive margins Spares surrounding normal tissues Accelerates treatment time No increase in perioperative complications* Split-course XRT *Haller, et al., Am J Otolaryngol., 1996

28. Day 1 5,6,7,8 8 29+ 50+ EndoscopyX & biopsy SurgeryX IORTX (7.5 Gy) EBRT X X X (B.I.D.- total 9.1 Gy) Cisplatin X X (80mg/m 2 ) (100mg/m 2 ) Schema - Intensification I

29. RESULTS - Intensification I* N = 37 Median time at risk = 21 months Compliance –Patient = 92% (34/37) –Protocol = 81% (30/37) *Schuller et al, Arch Otolaryngol Head Neck Surg. 1997

30. RESULTS - Intensification I* Loco-regional control –Overall = 97% (1/37) (local recurrence) –Completing protocol = 100% (0/30) Distant metastases = 16% (6/37) –Overall = 16% (6/37) –Completing protocol = 17% (5/30) *Schuller et al, Arch Otolaryngol Head Neck Surg. 1997

31. RESULTS - Intensification I* (Long-term follow-up) Median time at risk = 40 months Local control = 97% (36/37) Regional nodal control = 95% (35/37) Distant metastasis = 19% (7/37) 4-year overall survival = 45.9% *Grecula, et al., Cancer Investigation. 2001

32. Schema – Intensification III IR II acute hematologic toxicities unacceptable IR III modifications –Weekly paclitaxel 45 mg/m 2 over 3 hrs. Begin POD #6 9 cycles total –Postop cisplatin 30 mg/m 2 per day for 3 days 2 cycles total - 21 days apart Begin POD #27

33. Day 1-4 4 10 31 32 Surgery X IORT X (7.5 Gy) EBRT X X X 7 B.I.D. x (total 9.2 Gy) Cisplatin X X (30mg/m 2 ) (30mg/m 2 ) Paclitaxel X (45mg/m 2 weekly x 9) Schema - Intensification IV Total Duration of Treatment = 52 Days

34. Tumor Site (N=43) Oropharynx:46% (20) Oral cavity:35% (15) Hypopharynx: 19% (8) Overall Stage (N=43) Stage III:28% (12) Stage IV:72% (31)

35. T and N Distribution of the Enrolled Patients N0N1N2aN2bN2cN3Total T111 T21214 T365322422 T454211316 Total1110653843

36. RESULTS - Intensification IV N = 43 Median time at risk = 45 months (10.4 – 56.2) Compliance –Total Protocol = 53% (23/43) –Patient = 80% (34/43) Patients not completing protocol –Toxicity = 10 (23%) –Non-cancer death = 1 (2%) –Patient non-compliance = 9 (20%)

37. Copyright restrictions may apply. Schuller, D. E. et al. Arch Otolaryngol Head Neck Surg 2007;133:320-326.

38. RESULTS - Intensification IV Overall loco-regional control = 93% (40/43) Distant metastases –Overall = 9.3% (4/43) –Completing total protocol = 8.7% (2/23)

39. Toxicities of the Regimen (N=43) Operative Toxicity Type of Toxicity AcuteLate Grade-3Grade-4Grade-5Grade-3Grade-4Grade-5 Pharyngeal fistula 15 Flap hematoma 1 Flap donor site dehiscence 1 Flap survival failure 1 *Schuller, et al., Cancer, June 2002: 94-12, 3169-3178.

40. Toxicities of the Regimen (N=43) Nonoperative Toxicity Type of Toxicity AcuteLate Grade-3Grade-4Grade-5Grade-3Grade-4Grade-5 Hematologic 9 Infections requiring hospitalization 31 Mucositis 19 Gastrointestinal 1411 Cardiovascular 211 CVA 4 Neuropathy 1 Xerostomia Hearing loss 1 *Schuller, et al., Cancer, June 2002: 94-12, 3169-3178.

41. Schuller, D. E. et al. Arch Otolaryngol Head Neck Surg 2007;133:320-326. Kaplan-Meier survival analysis of intensification regimen 1

42. Schuller, D. E. et al. Arch Otolaryngol Head Neck Surg 2007;133:320-326. Kaplan-Meier survival analysis of intensification regimen 2

43. Schuller, D. E. et al. Arch Otolaryngol Head Neck Surg 2007;133:320-326. Kaplan-Meier survival analysis of intensification regimen 3

44. Functional Outcomes Speech – 100% –Laryngeal 88% (38/43) –Vocal prosthesis12%(5/43) Swallowing (N = 35 > 12 months NED) –Regular diet71% (25/35) –Soft diet20% (7/35) –No P.O. intake 9% (9/35) Permanent Tracheotomy - 0

45. Future Studies Quality of life/functional outcome measures Multi-institutional limited group Phase II Phase III trial

46. Will survival improve using intensified therapy with acceptable toxicities or do we need to look for alternative therapeutic approaches?

47. Prediction for this New Millennium Head and Neck Cancer – 1)Effective risk reduction therapies chemoprevention/smoke cessation 2)Enhanced rehabilitative techniques 3)More specific therapies increase cure/control rates

48. Improved Therapy for Head and Neck Cancer -- -- more surgery? -- more radiotherapy? -- more chemotherapy?... unlikely

49. Improved Therapy for Head and Neck Cancer -- -- better surgery -- better radiotherapy -- better chemotherapy... yes

50. We need more effective drugs.

51. There Is Tremendous Excitement About the Development of Targeted Therapies for Patients And genomics promises us more targets!!

52. 5-Year# Approved/% Period# Taken Into Trials Approved 1978-19833/268% 1984-19899/3426% 1990-199511/2446% 1996-200114/23*61% 2002-2003** Percent Of Agents Which We Have Taken Into Initial Phase I Trials In Patients Which Have Been Approved by the FDA *Too early. Best predictor for success: a new mechanism of action. Source: D. Von Hoff, May, 2003.

53. Misinformation Among Non-Surgical Oncologists Non-surgical treatment organ preservation –Anatomic organ preservation  organ function preservation Misinformation about surgical resection –Laryngeal cancer  total laryngectomy  aphonia –Tongue base cancer  total glossectomy  total laryngectomy –Partial/total pharyngectomy  permanent and total swallowing disability

54. Surgical Organ FUNCTION Preservation Speech – Vocal cord paralysis after vagus nerve resection  Injections  Laryngoplasty Partial laryngeal resection techniques – Endoscopic laser vaporization – Hemilaryngectomy w/laryngoplasty – Laser supraglottic laryngectomy – Supracricoid laryngectomy – Partial cricoid resection Total laryngectomy –Vocal restoration Result:: useful speech and swallowing (with aspiration)

55. Surgical Organ FUNCTION Preservation Swallowing – Partial oral/pharyngeal defects – flaps and/or grafts 1,2 Result: useful swallowing (with aspiration) and speech 1 Stein and Schuller, Laryngoscope, 1989. 2 Alvi and Myers, et al., Head Neck, 1996.

56. Surgical Organ FUNCTION Preservation Speech and Swallowing – Partial laryngopharyngeal defects – flaps (MC or free) 1, 2 – Total laryngopharyngeal defects – flaps (free) 3, 4, 5 Result: useful swallowing (with aspiration) and speech 1 Urken, et al., Arch Otolaryngol., 1997. 2 Schuller, et al., Laryngoscope, 1997. 3 Varvares, et al., Head Neck, 2000. 4 Jones, et al., Ann Plast Surg., 1996. 5 Rogers, et al., Head Neck, 2004.

57. Concerns about Non-Surgical Organ Preservation Therapy Larynx VA study sustained survival with organ preservation Non-laryngeal sites multiple phase II studies 1,2 Goal? –Organ preservation vs. organ preservation with improved survival? Different biological systems Larynx OC, ORO, HYPO 5 yr. Survival 65-70% 30-35% For non-laryngeal sites, is it currently justifiable/ethical to offer non-surgical organ preservation therapy based on phase II data with minimal chance of improving survival? 1 Roca, Eur J. Cancer, 1996. 2 Fuwa, Nippon Igaku Hoshasen Gakkai Zasshi, 2002.

58. Organ Preservation Strategies Laudable, need to continue to study Optimal goal function preservation and survival improvement Maximally aggressive utilization of – –Surgery –Radiotherapy –Chemotherapy...unacceptable toxicities and non- functioning/absent organs Need to recognize value of all modalities and develop trials using all modalities optimal results

59. Is clinical research worth the high cost? Advanced Non-Hodgkins Lymphoma* Standard Therapy: CHOP 30% survival (cooperative groups) Newer Therapies: m-BACOD (single institution) ProMACE-CytaBOM (single institution) MACOP-B (single institution) *Fisher, et al., NEJM, 328, 1993 55-65% survival

60. Is clinical research worth the high cost? But….limited follow-up, difficult administration, more toxic, more costly SWOG, ECOG Phase III Trial 1985 1138 patients899 eligible Conclusions No improvement to survival Slight increase in fatal toxic reaction (p =.09) CHOP still best available treatment* *Fisher, et al., NEJM, 328, 1993

61. Acknowledgements Amit Agrawal, M.D. Enver Ozer, M.D. John Grecula, M.D. Chris Rhoades, M.D.

62. Thank you for this honor.