Current Management of Head and Neck Squamous Cell Cancer

Kenneth Hu, MD 2011 ASTRO Spring Refresher Course Assoc Prof, Albert Einstein College of Medicine Beth Israel Medical Center, NY, NY

Course Objectives
To understand rationale for current treatment approaches Benefit of IMRT Future directions regarding risk adapted approaches

Disclosure
Speakers Bureau for Bristol Myers Squibb and Eli Lilly

Head and Neck Cancers

Most Common Sites Oropharynx

Larynx
Hypopharynx Oral Cavity

Nasopharynx

National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Head and Neck Cancers. Vol 1. 2005. Available at: http://www.nccn.org/professionals/physician_gls/PDF/head-andneck.pdf. Accessed December 14, 2005. Jemal A. CA Cancer J Clin. 2005;55:1030.

Background
> 600,000 worldwide cases per year with > 200,000 deaths 4th most common cancer worldwide US: 45,000/yr 60% Stage III/IV at diagnosis 11,000 deaths per year

Risk Factors
Primary risk factors Tobacco Alcohol
Males 2-4 times

Viral HPV (non-smokers tonsil)-40-60% EBV (nasopharynx)

General Principles #1
Goals:

Maximize Locoregional Control Preserve organ function Minimize toxicity of treatment

Multidisciplinary evaluation Early Stage-single modality (Surgery or Radiation) Advanced Stagemultimodality therapy Management of neck parallels primary site treatment

General Principles #2
Standard Approaches to improve radiation efficacy: Altered fractionated radiation Tumor Repopulation Minimize Treatment Time or Dose Escalate Concurrent Chemoradiation (cisplatin/taxane) Intensity Modulated Radiotherapy Newer approaches for risk adapted radiotherapy Targeted Biologic Induction chemotherapy

5 yr Disease-Free Survival (SEER Data 1998-1999)

Oral Cavity
Stage I Stage II Stage III Stage IV 71% 58% 45% 32%

Oropharynx
Stage I Stage II Stage III Stage IV 73% 58% 45% 32%

Larynx
Stage I Stage II Stage III Stage IV 84% 66% 52% 36%

Hypopharynx
Stage I Stage II Stage III Stage IV 53% 39% 36% 24%

AJCC Staging Handbook, 7th ed

Reasons for Death in Head and Neck Cancer Patients

Index cancermajor etiology
Locoregional failure 30-50% Distant Metastasis 20%

Comorbiditiescardiopulmonary, vascular Secondary cancers4-7% Treatment Related

Image-Based Neck Node Level Classification

Som et al, AJR, 2000

Incidence of Positive Lymph Nodes

Unilateral versus Contralateral node positive

Oral Cavity : Oropharynx: Larynx: Hypopharynx: Nasopharynx:

30% 60-75% 55% 75% 90%

5% 20-30% 20% 10% 50%

Percentage Incidence and Distribution of Pathologically Involved Nodes in a Clinical Node Negative Neck After Elective Radical Neck Dissection
I II III IV V

Oropharynx 2 25 19 8 2 n=48 Hypopharynx 0 13 13 0 0 n=24 Larynx 5 19 20 9 2.5 n=79 Oral Cavity 20 17 9 3 0.5 N=192 Shah, J.P et al. The patterns of cervical lymph node metastases from
squamous carcinoma of the oral cavity. Cancer, 1990. 66(1): p. 109-13

Percentage Incidence and Distribution of Pathologically Involved Nodes in a Clinical Node Positive after Therapeutic Radical Neck Dissection
I
Oropharynx n=165 14

II
71

III
42

IV
28

V
9

Larynx n=183
Hypopharynx n=104 Oral Cavity n=324

7
10 46

57
76 43

59
73 33

29
46 15

4
11 3

Shah, J.P., Patterns of cervical lymph node metastasis from squamous carcinomas of the upper aerodigestive tract. Am J Surg, 1990. 160(4): p. 405-9.

CARCINOMA OF THE NASOPHARYNX

Incidence and Epidemiology

< 1% of all Cancers in the U.S.A. Common among Southeast Asians, especially Chinese from the Southern Provinces of Kwantung, Kwangsi and Fukien.

Age : 45-55 Male : Female = 2-3 : 1 Incidence in Males /100,000 /yr : Hong Kong 28 U.S. (Connecticut) 0.6 Japan 0.4

Alaska Singapore

17.2 16.8

CARCINOMA OF NASOPHARYNX Lymph Node Metastases

70-90% incidence on presentation
40-50% bilateral Upper posterior cervical and subdigastric nodes are most frequently involved Retropharyngeal nodes are detected by MRI/CT scans

Epstein-Barr Virus
EBV associated with malignant transformation EBV Nuclear Antigen and viral DNA can be detected in tumor cells to diagnose NPC Serum EBV DNA detected by PCR can prognose survival and predict for distant metastasis (Lo Cancer Res 2000, 60(24) 6878-81) Serum EBV DNA monitor for treatment response and recurrence (Lo Cancer Res 1999, 59 (6) 1188-91)

CARCINOMA OF THE NASOPHARYNX

PRESENTING SYMPTOMS AND SIGNS

Cervical Adenopathy Unilateral Hearing Impairment Serous Otitis Media Nasal Obstruction Epistaxis Cranial Nerve Paralysis (CN V and VI Pain

Nasopharynx: Anatomical Boundaries

Upper boundary Sphenoid sinus, clivus Lower boundary Superior surface SP Posterior boundary Clivus, CVJ, prevertebral muscles Anterior boundary Posterior choana Lateral boundary Eustachian tube orifice, torus tubarius, fossa of Rosenmuller

Endoscopic View of Normal Nasopharynx

Flexible Endoscopic Images Left Nasopharynx Tumor

Landmarks: ET Eustachian Tube opening TT Toru Tubarius RF Rosenmuller Fossa

Patterns of Spread
Anatomically Difficult Location to Detect Early Locallycan extend down throat/skull base Spread to nodes of neck on same or both sides of neck in 90% of cases Spread to lungs/bones

INTERGROUP 99 (RTOG 88-17)

Al-Sarraf et al, JCO, 1998
S T R A T I F I Y
R T & N Stage A N D O M I

RT alone
(70 Gy)

AJCC (1992) III or IV M0

Performance Status Histology

Conv. Tech.

Z E

RT (70 Gy) + CDDP x 3

CDDP + 5FU x 3

INTERGROUP 99 (RTOG 88-17) TRIAL OF CHEMOTHERAPY FOR NPC Overall Survival - All Patients 76% RT + CT 46% RT p < .001
LRF: 33%10% DM: 35%13%

Study

Time Point 5 year

LocoRegional Control

PFS

DFS

DMF Rate 87%

OS

INT 0099 Wee (Sing.)

58%

74%

67%

2 year

90%

76%

87%

84%

Chan 5 year (PWH) Lin 5 year (Taiwan)

Lee (H.K.) 3 year

60%
74% 93% 72% 67% 89%

75%
79% 75%

70%
72% 76%

NPC: Meta-Analyses Chemotherapy and RT:

(Langendijk J.A., JCO 2004;22:4604-4612)

10 Randomized studies 4% increase in absolute survival at 5 years with the addition of chemotherapy LARGEST effects with CONCOMITANT therapy (20% increase in OS) Other Meta-analyses showed the same results!

NPC: Future Issues

Decrease Toxicity? Further Decrease Distant Mets? Screening/Vaccination

 Typical RT Fields:

Conventional Radiation Fields

Lee et al. IJROBP 40;1998:35

Late complications from RT for NPC

Xerostomia Hearing Loss Temporal Lobe Necrosis Oral and dental complications Pituitary hypofunction Neural complications Soft and hard tissue cx

New Radiation Technique: Intensity Modulated Radiation Therapy (IMRT)

Advantages Treats tumor and spares more normal tissue May allow dose escalation and tumor control Decrease long-term toxicity Disadvantage Small margins for error Special Expertise Longer Treatment time for patient

Organ Structures That Can Be Spared with IMRT

Parotids <24-26Gy (Eisbruch Submandibular Gland/Oral Cavity <39Gy (Murdoch-Kinch IJROBP 2008) Temporal lobe (Kam IJROBP 2003) Pituitary gland (Cheng, Int J. Ca 2001) Mean Constrictors <60Gy/Larynx (V50<50%) (Feng IJROBP 2007) Cochlea <48Gy (Chen, WC. Cancer 2006) Brachial Plexus (Hall IJROBP 2008)

IMRT for Nasopharynx

# Pts Med Local F/U (mo) 31 24 97% 100% Regional Distant Overall Metastas Surviva is l 98% 92% 28% 73% 100%

Lee Kwong

67 33

Kam
Wolden

64
74

29
35

92%
91%

98%
93%

21%
22%

90%
83%

Bevacizumab (avastin)
Monoclonal antibody that binds VERF, a.k.a, VEGF-A, a potent and specific growth factor for endothelial cells

Inhibits Neovascularization

Decreased Intersitial Fluid Pressure

RTOG 0615
R Node + or T2b E G I Histology: S WHO I-III T E R
Lee, Garden et al.
Concurrent: IMRT (70 Gy) CDDP (100mg/m2) x 3 cycles q 3 weeks + BV 15mg/kg q 3 weeks

Adjuvant:
CDDP (80 mg/m2) 5FU (1000 mg/m2) x 3 cycles q3 weeks

BV 15mg/kg q3 weeks
Maintenance:

BV 15mg/kg q 3 weeks for 9 cycles or 6 months

Updates and Emerging Concepts

Benefit of altered fractionated radiation Role of concurrent, induction chemotherapy and biologic therapies Impact of Human Papilloma virus on outcome Selection criteria for treatment deintensification and intensification

TONSIL: RT alone LOCAL CONTROL BY T-STAGE

T1 T2 T3 T4

81% to 100% 72% to 90% 50% to 72% 23% to 60%

Harrison 3rd Edition

SCC of Oropharynx
Parsons. Cancer 2002
Surgery+/-RT
BOT LC 79% 76%

RT +/- S

LRC
CSS Cx(Fatal) Tonsil LC LRC CSS Cx(Fatal)

60%
62% 32% (3.5%) 70% 65% 57% 23(3.2%)

69%
63% 3.8% (0.4%) 68% 69% 59% 6%(0.8%)

Altered Fractionation Schemes

Conventional Fractionation(CF)--5 daily treatments per week with 1.8-2.0Gy fraction size to 70Gy/7 weeks Accelerated Fractionation (AF)--reduce overall treatment time to minimize on treatment tumor repopulation 70Gy/ 6 weeks ; BID RT last weeks or DAHANCA regimen (6 tx/wk) Hyperfractionation (HF)--increase the number of fractions per given total dose to maximize DNA repair advantage of normal tissue and enhance tumor cell-cycle redistribution. 81.6Gy/7 wks

EORTC Protocol 22791 Hyperfractionation vs. Conventional Fractionation for Oropharyngeal Ca.
Sq. Cell Ca. Oropharynx R A N D O M I Z E
1. Conventional 2.0 Gy/fx/d

T.D.: 70 Gy/35 fx/7 wks

2. Hyperfractionation 1.15 Gy/fx B.I.D. T.D.: 80.5 Gy/70 fx/7 wks Horiot Radiother Onc 1992

T2 T3 N0, N1 < 3 cm M0

EORTC Protocol 22791 Hyperfractionation vs. Conventional Fractionation for Oropharyngeal Ca.
5-year Results Local Control T2N0-1 T3N0-1 HFx 59% 61% 51% CFx 40% 58% 18% p 0.02 0.67 0.001

Survival
Late Effects Free

40%
51%

30%
45%

0.08
0.72

RTOG 90-03: Phase III Study

1. Standard Fractionation T.D.: 70.0 Gy/35 fx/7 wks 2.0 Gy/fx Q.D. 2. Hyperfractionation T.D.: 81.6 Gy/68 fx/7 wks 1.2 Gy/fx B.I.D. 3. Accelerated Fractionation T.D.: 67.2 Gy/42 fx/6 wks (Split Course) 1.6 Gy/fx B.I.D. 2 wk split at 38.4 Gy 4. Accelerated Concomitant Boost T.D.: 72.0 Gy/42 fx/6 wks 1.8 Gy/fx/d to large field + 1.5 Gy/fx /d to boost field X 12 fxs. in last 2.5 wks
Fu, IJROBP 2000

1073 pts, Median followup 8 yrs

70Gy/7wks 81.6Gy/7wks 67.2Gy/6wks 72Gy/6wks

ASTRO 2008

Meta-Analysis: Fractionation
Conventional RT vs. HFX or Acc RT N=6515 patients 15 randomizes trials 1970-1998 Median F/U 6 years Modified radiotherapy led to a small but sig improvement in survival and LR control LR 7% benefit from 46 to 53% OS 3% benefit fro 36 to 39%
Baujat Cochrane Database Sys Rev 2010

Overgaard Lancet Oncol 2010

Rationale for Concurrent Chemoradiotherapy

Rationale: Overcome radioresistance and early eradication of microscopic distant metastases Synergistic effects of chemotherapy Interfere with cellular repair induced by RT (CDDP) Reduce population of hypoxic cells (Tirapazimine) Kill radioresistant cells in S phase and increase cell cycle synchronization (Hydroxyurea) Increase accumulation of cells at G2/mitosis phase where chemotherapy and RT are most effective (Taxanes) Decrease cells in S-phaseC225

Randomized Trial of Radiation Therapy Versus Concomitant Chemotherapy and Radiation Therapy for Advanced Stage Oropharynx Carcinoma
GORTEC Multicenter Trial 226 patients Stage III/IV (32%/68%) OPX Ca. Arm A: 70Gy/7wks (control) Arm B: 70Gy/7 wks + Carboplatin/5 Fluorouracil (70mgm/m2: 600mg/m2/dx4dx3cycles, wk 1, 4,7) Calais, JNCI 1999

French Trial: Oropharyngeal CA

(Denis et al, JCO, 2004)

Chemo + RT
Med. Surv. 20 mo 5 yr LRC
5 yr DFS 5 yr OS

RT Alone
13 mo 25%
p=.002 15% p=0.01 16% p=0.05

48%
27% 22%

RTOG 0129 Phase III Trial of Concurrent RT and CT for Advanced Head and Neck Cancer
Zubrod PS

S T R A T I F Y

0 or 1 Site : larynx vs non Nodal Status : N0 N1 or N2a-b N2c-N3

R A N D O M I Z E

Arm 1 : AFX-CB
72 Gy/42 FXS/6 wks plus CDDP 100 Mg/M2 days 1 and 22 Arm 2 : Concurrent 70 Gy + Cisplatin 100 mg/m2 I.V. on days 1, 22, 43.

IMRT OROPHARYNX
Author Year n Stage Chemo % Median FU months Loco-regional control

Chao (Wash U.) IJROBP 2004

Feng (Michigan) JCO 2010 De Arruda (MSKCC) IJROBP, 2005

74

76% III/IV 46% T3/4

III/IV

27%

33

87% (4 Yr)

73

100%

36

96% (3 Yr)

50

84% IV 37% T3/4

100%

24

92% (2 Yr)

Aspiration Risk and Dose to Pharyngeal

Constrictor and Larynx/Hypopharynx Risk for aspiration increases sharply after dose thresholds of 50-60Gy to the pharyngeal constrictor/larynx/hypopharynx

Eisbruch, et al., Int J Radiat Oncol Biol Phys. 2007;69(2 Suppl):S40-2. Feng, et al., Int J Radiat Oncol Biol Phys. 2007 Aug 1;68(5):1289-98. Levandag et al., Radiother Oncol. 2007 Oct;85(1):64-73. Schaner, et al. abstract 1099, ASTRO 2008 Gokhale, et al., abstract 1100, ASTRO 2008

.4

.5

.6

Probability Swallowing Problems

Cyberknife (3x + 4x)

.3

Brachytherapy implant
No BT / No Cyberknife

.2

.1

4x 3x

0 0

10

20

30

40

50

60

70

80

Dose superior constrictor muscle (Gy)

Levendag PC, et al. Radiother Oncol. 2007

Dysphagia and Aspiration after Chemoradiotherapy for Head and Neck Cancer: Which Anatomic Structures Are Affected and Can They Be Spared by IMRT?

Eisbruch, A. et al., IJROBP V 60, No 5, 1425-1439, 2004

73 III/IV Opx 70Gy/7wks + taxol/carbo/wk

Med F/U 36mo 3yr LRC 96% DFS 88%

Feng JCO 2010

PEG dependence 1.4% at 1yr 5 pts with strictures 8 pts with pneumoniaall silent aspirators

Dysphagia related to dose to PC,Lx, Esoph Neck dissection/smoking/t-stage

Ang et al, Cancer Res 62:7350-7356, 2002

NEJM 2006

Phase III C225 /RT Trial for Advanced HNC

Median f/u 38 months Cetuximab/RT superior compared to RT Locoregional control at 1 yr (69% vs 59%)
2yr (56% vs 48%) Larynx Preservation in 171 Hpx/Lx
2yr (92 vs 83%) 3yr (88vs 80%)

2 yr OS: 62 vs. 55%; 3 yr OS: 57 vs. 44% Median OS: 54 months vs. 28 months (p=.02) Bonner et al, ASCO 2004 and 2005

Bonner Lancet Oncol 2010

RTOG 0522Phase III Trial of Concurrent RT and CT for Advanced Head and Neck Cancer
On-Going R A N D O M I Z E Zubrod PS

S T R A T I F Y

0 or 1 Site : larynx vs non Nodal Status : N0 N1 or N2a-b N2c-N3

Arm 1 : AFX-CB 72 Gy/42 FXS/6 wks plus CDDP 100 Mg/M2 days 1 and 22 Arm 2 : As above + C225

TAX 324: Sequential Combined Modality Therapy

TPF vs PF Followed by Chemoradiotherapy
Posner NEJM 2007 R A N D O M I Z E
T P
Carboplatinum - AUC 1.5 Weekly

F
Surgery as Needed

P F

Daily Radiotherapy

TPF: Docetaxel 75D1 + Cisplatin 100D1 + 5-FU 1000 CI- D1-4 Q 3 weeks x3 PF: Cisplatin 100 + 5-FU 1000 Q 3 weeks x 3

TAX324 : Survival
100 90 80

Survival Probability (%)

70 60 50 40 30 20 10 0

Log-Rank P = 0.0058 Hazard Ratio = 0.70

TPF 67% PF TPF (n=255) 54%

PF (n=246)

TPF 62%
PF 48%

12

18

24 30 36 42 48 Survival Time (months)

163 130 136 107 105 85 72 57 52 36

54
45 32

60
37 28

66
20 10

72
11 7

Number of patients at risk TPF: 255 234 196 176 PF: 246 223 169 146

Head and Neck Cancer

Chemotherapy Meta-analysis: 63 Studies
No. of Patients (N = 10,717) 1854 5245 5-year Survival Benefit (%) 1 2

Group
Adjuvant chemotherapy Neoadjuvant chemotherapy

Concurrent radiation 3727 therapy and chemotherapy

*P<.001

8*

Bourhis J et al. Int J Radiat Oncol Biol Phys. 1998;42(suppl):145. Abstract 42.

Human Papilloma Virus in Oropharynx Cancer

HPV found in 40-60% of all oropharynx cancer HPV positive oropharynx ca correlates with Marijuana use, not tobacco use High risk sexual behavior 5-10 year younger patients, M:F equal Basaloid, poorly differentiated histology HPV-16 subtype in 85-90% (HPV 31,33,35 in rest)
D'Souza, G., N Engl J Med, 2007. 356(19): p. 1944-56. Hammarstedt, Int J Cancer, 2006. 119(11): p. 2620-3. Gillison, J Natl Cancer Inst, 2008. 100(6): p. 407-20. Fakhry, C. and Gillison, M.L., J Clin Oncol, 2006. 24(17): p. 2606-11. Gillison, M.L., J Natl Cancer Inst, 2000. 92(9): p. 709-20.

3yr OS 82% vs 57%

3yr PFS 74% vs 43%

Ang NEJM 2010

Risk Stratify by HPV, Tobacco and T/N Stage

RPA

3yr OS 93% vs 71% vs 46%

Dose Deintensification for HPV+ Oropharynx Cancer

ECOG 1308: Taxol/Carbo/C225 induction
IF complete response decrease total dose GTV 54Gy+C225 IF partial response, standard dose 70Gy + C225

RTOG: Phase III: 70Gy: Cisplatin vs Cetuximab

Cancer of the Larynx/Hypopharynx /Oral Cavity

Kenneth Hu,M.D. Beth Israel Medical Center NY, NY

CARCINOMA OF THE LARYNX

INCIDENCE OF LYMPH NODE METASTASES Site Incidence

Supraglottis Positive Nodes Bilateral Nodes Glottis

55 % 16 %

T4
Subglottis

T1 < 2% T2 3-7 % T3 15-20 % 20-30 % 10-30 %

T1-2NO Glottic Treatment Technique

LOCAL CONTROL OF T1 BY FRACTION SIZE

100

94% 92% 81% 79%

2.25Gy 2.0-2.24 Gy 1.8-1.99 Gy < 1.8 Gy

80

Local Control (%)

60

40

P = 0.04

20

10

Time from Treatment (Yr.)

Le IJROBP 1997

LOCAL CONTROL OF T1 LESIONS BY OVERALL TIME

100

98 % 84%

43 D > 50 D 44-50 D

80

83%

Local Control (%)

60

p = 0.04
40

20

10

Time from Treatment (Yr.)

LOCAL CONTROL OF T2 LESIONS BY FRACTION SIZE

100

2.25 Gy

80

2.0-2.24 Gy 1.80-1.99 Gy

Local Control (%)

60

40

< 1.80 Gy

20

0 0 2 4 6 8 10

Time from Treatment (Yr.)

LOCAL CONTROL OF T2 LESIONS BY OVERALL TIME

100

100%

43 D

80

Local Control (%)

70%
60

66%

44-50 D > 50 D

40

20

10

Time from Treatment (Yr.)

LOCAL CONTROL FOR T2 GLOTTIC BY CORD MOBILITY

100 80

79% Normal

Local Control (%)

60

45%
40

Impaired

20

p = 0.008

0 0 2 4 6 8 10

Time from Treatment (Yr.)

LOCAL CONTROL FOR T2 LESIONS BY SUBGLOTTIC EXTENSION

100 80

77% Without SGE

Local Control (%)

60

58% With SGE

40

p = 0.02
20

SGE: Subglottic Extension

0 2 4 6 8 10

Time from Treatment (Yr.)

2006 ASTRO

RTOG 95-12 HYPERFRACTIONATION FOR T2 VOCAL CORD CA

R A N D O M I Z E

S T R A T I F Y

1. Conventional Fractionation:

Stage 1. T2a

2 Gy/fx/d to 70 Gy/35 fx/7 wks LC:

2. T2b

2. Hyperfractionation:
1.2 Gy/fx BID to 79.2 Gy/66 fxs/6.5 wks

Supraglottic Larynx Treatment

Carcinoma of the Supraglottis

% Local Control with Radiotherapy (and Surgical Salvage)
1st Author
Harwood Wall

T1
71 89

T2
68 74

T3
56 70

T4
41-52 46

Mendenhall
Wang : Q.D. B.I.D.

100
74 84

81 (88)
61 83

61 (83)
56 71

33 (67)
29 84

Role of Chemotherapy for Larynx/Hypopharynx Preservation

VA LARYNGEAL CA. STUDY

Surgery R A N D O M I Z E Radiation Therapy
PR Surgery

CR or PR (3rd Cycle of Chemo)

Induction Chemotherapy (2 Cycles)

Radiation Therapy CR

< PR

Surgery

Radiation

Induction Chemotherapy: Cisplatin and 5-FU

Results of VA Protocol
No Difference in 2 year survival 68% Larynx Preservation in 64% in CTRT group with:
Fewer Distant Metastases Higher Local Recurrence Salvage in 3/4
Arch Otol 124;964-971, 1998

Long-term (10yr) Quality of Life Follow-Up

speech significantly better in CTRT group same incidence of swallowing difficulties in both groups Less pain and depression with better global mental health in CT RT group NEJM 1991;324:1685-90

RTOG 91-11 Phase III Trial to Preserve the Larynx

S T R A T I F Y
R A Glottic Supraglottic N D T Stage: O T2 T3 M Early T4 I N Stage: Z N0, N1 E
Location:
N2, N3 Arm 1 : Neoadjuvant CT + RT CR, PR CP + 5-FU RT X 1 Cycle CDDP + 5-FU X 2 Cycles NR Surgery RT

Forastiere NEJM 2003

Arm 2 : RT + CDDP
Arm 3 : RT Alone

RTOG 91-11
VA 2 year Laryng-FS 2 year LR control 5 year DM 5-yr. Survival 75% 61% 15% 55% CCRT 88% 78% 12% 54% RT 70% 56% 22% 56%

Median F/U 3.8 years

* Estimated from survival curves

University of Florida 101 pts with T1-2 Pyriform sinus SCC Minimum f/u 2yrs; 87% 5yr f/u. RT alone:conventional fractionation to 66Gy or hyperfractionated 1.2 bid to 74Gy Planned neck dissection if LN+

Amdur Head Neck 2001

Stage I

T1 T2

II

III IVa IVb

 202 pts (Stage III: 57%, IV:37%) Arm A: Surgery (TL+PP)post-op RT Arm B: CDDP/5FU x 2-3 cycles if CR RT 70Gy/7wks alone 54% CR after induction chemotherapy T2=82% (n=22); T3=48% (n=71), T4=0%(n=4)

J Natl Cancer Inst 88:890-9,1996

Results
Median F/U 51mos Local failure arm A:B 12%:17% (p=ns) Regional failure arm A:B 19%:23% (p=ns) Distant Metastasis:A:B 36%:25% (p=0.04) Median OS arm A:B 25mo: 44mos 5yr OS arm A:B 35%:30% (p=ns) Larynx Preservation 3yr/5yr: 42%/35%

GORTEC 2000-01 Phase III: Induction TPF vs PF for Organ Preservation in Hypopharyx/Larynx 213 LX or HPX requiring Total Laryngectomy Randomized to 3 cycles:
PF: CDDP (100mg/m2/d1) and 5 Fluorouracil (100mg/m2d1-5) q 3wks TPF: Taxotere (75/mg/m2d1),CDDP (75mg/m2/d1) and 5 Fluorouracil (750mg/m2d1-5) q 3wks If CR or PR & recovery of normal vocal cord mobility RT 70Gy/7wks
Calais, G. et al ASCO 2006

Multidisciplinary Head and Neck Symposium, 2010

GORTEC 2000-01:Results
Median F/U 61 mos Compliance 82% (TPF) vs 67% (PF) Overall response: 83% (TPF) vs 61% (PF) (p=0.0013) Complete response: 61% (TPF) vs 47% (PF)

5yr Larynx Preservation:74% (TPF) vs 51% (PF)

5yr Larynx and esophageal dysfunction free survival measured by VHI and EORTC QOL 30 60% (TPF) vs 39% (PF) (all) 36% (TPF) vs 21% (PF) (alive) 8% PEG; 3% trach

IMRT: Early Stage Glottic Larynx

Advantage:
Carotid sparing

Disadvantage:
Geographical miss from contouring or intrafraction motion Toxicity from dose inhomogeneity

Gomez Radiat Oncol 2010 Chera IJROBP 2010 Rosenthal IJROBP 2010

IMRT: T1 Glottic Ca
Inferior Constrictor D50 48Gy vs 61.5Gy 2D R carotid a D50 8Gy vs 60Gy 2F-Conventional

IMRT

3F-IMRT

D50: 8Gy

D50: 60Gy

IMRT for Advanced Stage Lx/HPX

Daly Head and Neck 2011

Studer IJROBP 2011 Miah IJROBP 2011 Lee IJROBP 2007

Toxicity IMRT Larynx/Hypopharynx

Med F/U PEG-d Trach/TL Esoph Aspiration Stenosis Risk Lee 26mo 26% 3% (gr 5)

Studer 21mo
Daly Miah 30mo 36mo

3%
2% 5%

3%/2%
17% 17%

Larynx Preservation
Conclusions

RT alone for early stage disease Concurrent chemoradiotherapy is the treatment for locally advanced larynx cancer No significant difference in survival between CCRT, induction, or RT alone due to excellent surgical salvage Induction vs concurrent chemotherapy considered for advanced hypopharynx Patients with T4a disease should consider upfront surgery then post-op RT+/-chemotherapy Role of IMRT being evaluated in early stage, yields promising locoregional control in adv stage ? Increased toxicity

T4a N+ Glottic Supraglottic Surgery Preferred + Post-OP

Treatment Paradigm Oral Cavity Cancer

Upfront surgical resection followed by radiation +/chemotherapy Is the preferred treatment of choice

Post Op Radiation Therapy (PORT)

Intermediate risk factors: oral cavity,multiple nodes, LVI, PNI, level IV nodes, close margins, T3-4 High risk factors: ECE or positive margins Low risk: early stage, single node, no adverse pathologic factors

Post Op Radiation Therapy (PORT)

Primary: Close or + Margin, PNI, LVI T3/4 Oral cavity/Hypopharynx Lymph Node Extracapsular spread Multiple nodes Low level IV nodes

IJROBP 2001

High risk and total treatment time

EORTC and RTOG Phase III Studies CDDP + RT vs RT for High Risk Postop
High Risk Post-op:
EORTC 22931 : ECE, + margin, LVI, PNI, Level IV/V if OC,OPX, Stage III/IV
RTOG 95-01 : ECE, + margin, multiple nodes

60-66Gy in 2Gy fractions

60-66Gy in 2Gy fractions + CDDP 100mg/m2 wk 1,4,7

Cooper NEJM 2004; Bernier NEJM 2004

Post-operative Chemoradiation vs Radiation: Phase III Trials

RTOG95-01 # patients OPX /OC/ /LX/HPX % T3-4 % N2-3 459 42%/27%/21%/10% 61% 94% EORTC22931 334 30%/26%/22%/20% 66% 57%

% with ECE and/or + margins

RT: %receiving 66Gy

59%
13%

70%
91%

Post-op CT/RT vs RT: Results of EORTC/RTOG Phase III Trials

RTOG95-01 EORTC22931

Median follow up
Locoregional failure

46mo
Outcomes(CT/RTvs RT) 3yr: 22% vs 33% (p=0.01)

60 months
Outcomes(CT/RTvs RT) 5yr: 18%vs 31% (p=0.007)

Disease-free Survival
Overall Survival Distant Metastases >Grade 3 acute toxicity All late toxicity

3yr: 47% vs 36% (p=0.04)

3yr: 56% vs 47% (p=0.09) 3yr: 20% vs 23% (P=0.46) 77% vs 34% (p<0.0001) 21% vs 17% (p=0.29)

5yr: 47% vs 36% (p=0.04)

5yr: 53% vs 40% (p=0.02) 5yr: 21% vs 24% (p=0.61) 44% vs 21% (p=0.001) 38% vs 41% (p=0.25)

RTOG 0234: Phase II Randomized Trial of Post-op Chemoradiation plus C225 for High Risk SCC of Head and Neck
203 pts with ECE (59%),+ margin (41%), or >2LN+ 60Gy: C225+cddp vs C225+taxotere Median f/u 2.5yrs
Kies ASTRO 2009

Results: RTOG 0234

CDDP/C225 Taxotere/C225

Locoregional failure Disease-free Survival Compared to 95-01

2yr: 21% 2yr: 57% HR 0.85 p=0.19 2yr: 69% 2yr: 26%

2yr: 20% 2yr: 66% HR 0.72 p=0.031 2yr: 79% 2yr: 13%

(Cddp+RT)
Overall Survival Distant Metastases >Grade 3 acute heme/derm/mucositis 28%/39%/37% 14%/39%/33%

RTOG 0920: Randomized Study of Post-op RT +/_ C225 in Intermediate Risk Patients
Close Margins, Multiple Nodes, LVI, PNI 2 arms:
Post-op RT 60-66Gy Post-op RT 60-66Gy + 11 weeks of C225 (loading, during RT and 4 weeks after RT)

Definitive Treatment of Oral Cavity Cancer: Brachytherapy

Definition: Direct placement of radiation isotopes into a tumor Optimal therapeutic ratio (dose to tumor: dose to normal tissue)
High dose conformality Dose escalation (77-80Gy)

Disadvantages of Brachytherapy
Treats limited volumes Requires special expertise Radiation Exposure to Hospital Personnel (low dose rate)

Oral Tongue Cancer Local Control Comparison Radiation vs. Surgery

90 80 70 60 50 40 30 20 10 0 T1 T2 T3 RT (Curie) Surg (MSKCC)

Decroix Cancer 1981

Conclusion
Pathologic risk stratification established LVI/PNI/Multiple LN without ECE/close margins require RT ? Benefit of C225 ECE or Positive Margins need addition of chemotherapy (high dose cddp) to RT Brachytherapy should be considered in definitively treated oral cavity cancers