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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Source: Ohio Department of Health Data 2004, U.S. Census Bureau 2004, KSA Analysis

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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.