surgery as a contemporary therapeutic modality for head and neck cancer southern ohio medical center...
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Surgery as a ContemporaryTherapeutic 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
Master Plan - 2016
Cancer in Ohio
Cancer is the #1 killer in Ohio10th highest rate in US for cancer deaths for women13th highest rate in US for cancer deaths for men6th highest death rate for breast cancer6th highest death rate for colorectal cancerEvery hour of every day, 7 people in Ohio are diagnosed with cancerEvery hour of every day, 3 people in Ohio die from cancer
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
Cancer in Ohio
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Ohio’s population is aging
Source: U.S. Census Bureau, March 2005
Source: Ohio Department of Health Data 2004, U.S. Census Bureau 2004, KSA Analysis
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2001 Ohio Cancer Cases and Incidence
Cancer in Ohio
Cancer incidence increases as the population ages
OSU Comprehensive Cancer Center
NCI designated “Comprehensive” since 1976One of only 39 comprehensive cancer centers in the USAOnly 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 collegesGenerates, on average, more than $100M annually in cancer-relevant research funding
The OSU Cancer Program
James Cancer Hospital and Solove Research Institute
Research teaching hospital training the doctors of tomorrowOnly 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
Background Information
Therapeutic Options
1. Surgery – locoregional
2. Radiotherapy – locoregional
3. Chemotherapy – Systemic
4. Chemoradiotherapy – locoregional
BackgroundHead and Neck Cancer
Survival Improvement NO
Failure Site*Local/Regional 23%Distant 18%
*Laramore, et al., Int. J. Rad. Onc. Biol. Phys., 23(4), 1992
BackgroundHead and Neck Cancer
Quality of Life ImprovementProbably
Patient ComplianceMajor Challenge (36%)*
*Laramore, et al., Int. J. Rad. Onc. Biol. Phys., 23(4), 1992
Definition of Terms
Phase I Trial - ToxicityRecurrent/metastatic, any type/site
Phase II Trial - ResponseRecurrent/metastatic, type/site specific
Phase III Trial - SurvivalPreviously untreated, controlled, randomized
Research Capabilities
Single Institutions Pilot Studies
Individual Cooperative Group Phase I/II Trials
Multiple Cooperative Groups (HNI) Phase III Trials
Treatment Modalities
Surgery
Radiation Therapy
Chemotherapy
Chemoradiotherapy
. . . Non-specific “bigger is better”
Tx Modalities in New Millennium
Surgery organ preservation/ reconstructive techniques
Radiation Therapy conformal, intraoperative, intensity modulated
Chemotherapy molecular targeted therapies
. . . specific and focused
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
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
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
Goals of Intensification Regimen
Intensify treatment to primary tumor, neck nodes and distant sites
Improve patient compliance
Assess toxicity related to therapy
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
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
Day 1 5,6,7,8 8 29+ 50+Endoscopy X& biopsy
Surgery X
IORT X (7.5 Gy)
EBRT X X X (B.I.D.- total 9.1 Gy)
Cisplatin X X (80mg/m2) (100mg/m2)
Schema - Intensification I
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
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
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
Schema – Intensification III
IR II acute hematologic toxicities unacceptable
IR III modifications– Weekly paclitaxel 45 mg/m2 over 3 hrs.
• Begin POD #6• 9 cycles total
– Postop cisplatin 30 mg/m2 per day for 3 days• 2 cycles total - 21 days apart• Begin POD #27
Day 1-4 4 10 31 32Surgery X
IORT X (7.5 Gy)
EBRT X X X
7 B.I.D. x (total 9.2 Gy)
Cisplatin X X (30mg/m2) (30mg/m2)
Paclitaxel X (45mg/m2 weekly x 9)
Schema - Intensification IV
Total Duration of Treatment = 52 Days
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)
T and N Distribution of the Enrolled Patients
N0 N1 N2a N2b N2c N3 Total
T1 1 1
T2 1 2 1 4
T3 6 5 3 2 2 4 22
T4 5 4 2 1 1 3 16
Total 11 10 6 5 3 8 43
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%)
Copyright restrictions may apply.
Schuller, D. E. et al. Arch Otolaryngol Head Neck Surg 2007;133:320-326.
RESULTS - Intensification IV
Overall loco-regional control = 93% (40/43)
Distant metastases– Overall = 9.3% (4/43)– Completing total protocol = 8.7% (2/23)
Toxicities of the Regimen (N=43)
Operative Toxicity
Type of Toxicity
Acute Late
Grade-3 Grade-4 Grade-5 Grade-3 Grade-4 Grade-5
Pharyngeal fistula 1 5
Flap hematoma 1
Flap donor site dehiscence 1
Flap survival failure 1
*Schuller, et al., Cancer, June 2002: 94-12, 3169-3178.
Toxicities of the Regimen (N=43)
Nonoperative Toxicity
Type of Toxicity
Acute Late
Grade-3 Grade-4 Grade-5 Grade-3 Grade-4 Grade-5
Hematologic 9
Infections requiring hospitalization 3 1
Mucositis 19
Gastrointestinal 14 1 1
Cardiovascular 2 1 1
CVA 4
Neuropathy 1
Xerostomia
Hearing loss 1
*Schuller, et al., Cancer, June 2002: 94-12, 3169-3178.
Schuller, D. E. et al.Arch Otolaryngol Head Neck Surg 2007;133:320-326.
Kaplan-Meier survival analysis of intensification regimen 1
Schuller, D. E. et al. Arch Otolaryngol Head Neck Surg 2007;133:320-326.
Kaplan-Meier survival analysis of intensification regimen 2
Schuller, D. E. et al. Arch Otolaryngol Head Neck Surg 2007;133:320-326.
Kaplan-Meier survival analysis of intensification regimen 3
Functional Outcomes
• Speech – 100%– Laryngeal 88% (38/43)– Vocal prosthesis 12% (5/43)
• Swallowing (N = 35 > 12 months NED)– Regular diet 71% (25/35)– Soft diet 20% (7/35)– No P.O. intake 9% (9/35)
• Permanent Tracheotomy - 0
Future Studies
Quality of life/functional outcome measures
Multi-institutional limited group Phase II
Phase III trial
Will survival improve using intensified therapy with acceptable toxicities or
do we need to look for alternative therapeutic approaches?
Improved Therapy for Head and Neck Cancer --
-- more surgery?
-- more radiotherapy?
-- more chemotherapy?
. . . unlikely
Improved Therapy for Head and Neck Cancer --
-- better surgery
-- better radiotherapy
-- better chemotherapy
. . . yes
We need more effective drugs.
There Is Tremendous Excitement About the Development of Targeted
Therapies for Patients
And genomics promises us more targets!!
5-Year # Approved/ % Period # Taken Into Trials Approved
1978-1983 3/26 8%
1984-1989 9/34 26%
1990-1995 11/24 46%
1996-2001 14/23* 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.
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
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)
Surgical Organ FUNCTION Preservation
• Swallowing– Partial oral/pharyngeal defects – flaps and/or
grafts1,2
Result: useful swallowing (with aspiration) and speech
1Stein and Schuller, Laryngoscope, 1989.2Alvi and Myers, et al., Head Neck, 1996.
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 speech1Urken, et al., Arch Otolaryngol., 1997.2Schuller, et al., Laryngoscope, 1997.3Varvares, et al., Head Neck, 2000.4Jones, et al., Ann Plast Surg., 1996.5Rogers, et al., Head Neck, 2004.
Concerns about Non-Surgical Organ Preservation Therapy
• Larynx VA study sustained survival with organ preservation
• Non-laryngeal sites multiple phase II studies1,2
• 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?
1Roca, Eur J. Cancer, 1996.2Fuwa, Nippon Igaku Hoshasen Gakkai Zasshi, 2002.
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
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
Is clinical research worth the high cost?
But….limited follow-up, difficult administration, more toxic, more costly
SWOG, ECOG Phase III Trial 1985 1138 patients 899 eligible
ConclusionsNo improvement to survivalSlight increase in fatal toxic reaction (p = .09)CHOP still best available treatment*
*Fisher, et al., NEJM, 328, 1993
Acknowledgements
Amit Agrawal, M.D.Enver Ozer, M.D.
John Grecula, M.D.Chris Rhoades, M.D.
Thank you
for
this honor.