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Current Management of Headand Neck Squamous Cell

Cancer

Kenneth Hu, MD

2011 ASTRO Spring Refresher Course

Assoc Prof, Albert Einstein College of MedicineBeth Israel Medical Center, NY, NY



Course Objectives

• To understand rationale for current

treatment approaches

• Benefit of IMRT

• Future directions regarding risk adapted

approaches



Disclosure

• Speaker’s Bureau for Bristol Myers Squibb

and Eli Lilly



Head and Neck CancersMost Common Sites

• Oropharynx

• Larynx

• Hypopharynx

• Oral Cavity

• Nasopharynx

National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncolo gy. Head and Neck

Cancers. Vol 1. 2005. Available at: http://www.nccn.org/professionals/physician_gls/PDF/head-and-

neck.pdf. Accessed December 14, 2005. Jemal A. CA Cancer J Clin . 2005;55:10 –30.



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



• Primary risk factors

– Tobacco

– Alcohol – Males 2-4 times

– Viral

• HPV (non-smokers tonsil)-40-60%

• EBV – (nasopharynx)

Risk Factors



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



• Stage I 73%

• Stage II 58%

• Stage III 45%

• Stage IV 32%

Oral Cavity Oropharynx

Hypopharynx

AJCC Staging Handbook, 7th ed

Larynx

•Stage I 53%

• Stage II 39%

• Stage III 36%

• Stage IV 24%

•Stage I 84%

• Stage II 66%

• Stage III 52%

• Stage IV 36%

• Stage I 71%

• Stage II 58%

• Stage III 45%

• Stage IV 32%

5 yr Disease-Free Survival

(SEER Data 1998-1999)



Reasons for Death in Head and Neck

Cancer Patients• Index cancer — major etiology

– Locoregional failure 30-50%

– Distant Metastasis 20%

• Comorbidities — cardiopulmonary, vascular

• Secondary cancers — 4-7%

• 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 : 30% 5%

• Oropharynx: 60-75% 20-30%• Larynx: 55% 20%

• Hypopharynx: 75% 10%

• Nasopharynx: 90% 50%



Percentage Incidence and Distribution of

Pathologically Involved Nodes in a Clinical

Node Negative Neck After Elective Radical Neck Dissection

I II III IV VOropharynx

n=482 25 19 8 2

Hypopharynx

n=240 13 13 0 0

Larynxn=79

5 19 20 9 2.5

Oral Cavity

N=19220 17 9 3 0.5

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 NeckDissection

I II III IV VOropharynx

n=16514 71 42 28 9

Larynx n=183 7 57 59 29 4

Hypopharynxn=104

10 76 73 46 11

Oral Cavity

n=32446 43 33 15 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.



• < 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 Alaska 17.2

U.S. (Connecticut) 0.6 Singapore 16.8

Japan 0.4

Inc idence and Epidem iology

CARCINOMA OF THE NASOPHARYNX



CARCINOMA OF NASOPHARYNX

Lymph Node Metas tases

• 70-90% incidence on presentation

• 40-50% bilateral• Upper posterior cervical and subdigastric

nodes are most frequently involved

• Retropharyngeal nodes are detected byMRI/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

res onse and recurrence Lo Cancer Res 1999 59 6 1188-91



•Cervical Adenopathy

•Unilateral Hearing Impairment

•Serous Otitis Media

•Nasal Obstruction

•Epistaxis

•Cranial Nerve Paralysis (CN V and VI

•Pain

PRESENTING SYMPTOMS AND SIGNS

CARCINOMA OF THE

NASOPHARYNX



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



Landmarks: ET – Eustachian Tube opening

TT – Toru TubariusRF – Rosenmuller Fossa

Endoscopic View of Normal Nasopharynx

Flexible Endoscopic

ImagesLeft Nasopharynx Tumor



Patterns of Spread

• Anatomically Difficult Location to Detect

Early

• Locally — can 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

R

A

N

DO

M

I

Z

E

S

T

R

AT

I

F

I

Y

T & N Stage

PerformanceStatus

Histology

RT alone

(70 Gy)

RT (70 Gy) +CDDP x 3

AJCC

(1992)

III or IV

M0

Conv. Tech.

CDDP + 5FU x 3



INTERGROUP 99 (RTOG 88-17)TRIAL OF CHEMOTHERAPY FOR NPC

Overall Survival - All Patients

RT46%

76%

p < .001

RT + CT

LRF: 33%10%

DM: 35%13%

St d Ti L PFS DFS DMF OS



Study Time

Point

Loco-

Regional

Control

PFS DFS DMF

Rate

OS

INT0099

5 year 58% 74% 87% 67%

Wee

(Sing.)

2 year 90% 76% 87% 84%

Chan

(PWH)

5 year 60% 75% 70%

Lin

(Taiwan)

5 year 74% 72% 89% 79% 72%

Lee

(H.K.)

3 year 93% 67% 75% 76%

NPC M A l



NPC: Meta-Analyses

Chemotherapy and RT:

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

• 10 Randomized studies

• 4% increase in absolute survival at 5 yearswith 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



Conventional Radiation Fields• Typical RT 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 RadiationTherapy (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



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 MedF/U(mo)

Local Regional DistantMetastasis

OverallSurvival

Lee 67 31 97% 98% 28% 73%

Kwong 33 24 100% 92% 100%

Kam 64 29 92% 98% 21% 90%

Wolden 74 35 91% 93% 22% 83%

Be aci mab (a astin)



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 E

G

I

S

T

E

R

RTOG 0615

Node + or ≥ T2b

Histology:

WHO I-III

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

Lee, Garden et al.



Updates and Emerging

Concepts

• Benefit of altered fractionated radiation

• Role of concurrent, inductionchemotherapy and biologic therapies

• Impact of Human Papilloma virus on

outcome

• Selection criteria for treatment

deintensification and intensification



T1 81% to 100%

T2 72% to 90%

T3 50% to 72%T4 23% to 60%Harrison 3rd

Edition

TONSIL: RT alone

LOCAL CONTROL BY T-STAGE

SCC f O h



SCC of OropharynxParsons. Cancer 2002

Surgery+/-RT RT +/- SBOT

LC 79% 76%

LRC 60% 69%

CSS 62% 63%

Cx(Fatal) 32% (3.5%) 3.8% (0.4%)

Tonsil

LC 70% 68%

LRC 65% 69%

CSS 57% 59%

Cx(Fatal) 23(3.2%) 6%(0.8%)



Altered Fractionation Schemes• Conventional Fractionation(CF)--5 daily

treatments per week with 1.8-2.0Gy fractionsize to 70Gy/7 weeks

• Accelerated Fractionation (AF)--reduce overalltreatment time to minimize on treatment tumorrepopulation 70Gy/ 6 weeks ; BID RT lastweeks or DAHANCA regimen (6 tx/wk)

• Hyperfractionation (HF)--increase the number

of fractions per given total dose to maximizeDNA repair advantage of normal tissue andenhance tumor cell-cycle redistribution.81.6Gy/7 wks



EORTC Protocol 22791Hyperfractionation vs. Conventional

Fractionation for Oropharyngeal Ca.

Sq. Cell Ca.

Oropharynx

T2 T3N0, N1 < 3 cm

M0

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

R

A

N

D

O

MI

Z

EHoriot Radiother Onc 1992

EORTC Protocol 22791



EORTC Protocol 22791Hyperfractionation vs. ConventionalFractionation for Oropharyngeal Ca.

5-year Results HFx CFx p

Local Control 59% 40% 0.02

T2N0-1 61% 58% 0.67

T3N0-1 51% 18% 0.001

Survival 40% 30% 0.08

Late Effects Free 51% 45% 0.72

RTOG 90-03: Phase III Study



RTOG 90 03: Phase III Study1. Standard Fractionation T.D.: 70.0 Gy/35 fx/7wks

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/6wks (Split Course)

1.6 Gy/fx B.I.D. 2 wk split at 38.4 Gy

4. Accelerated Concomitant Boost T.D.: 72.0Gy/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 wksFu, IJROBP 2000



1073 pts, Median followup 8 yrs

70Gy/7wks 67.2Gy/6wks81.6Gy/7wks 72Gy/6wks

ASTRO 2008

Meta-Analysis:



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



R i l f C



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 phasewhere chemotherapy and RT are most effective

(Taxanes)

– Decrease cells in S-phase — C225



Randomized Trial of Radiation Therapy

Versus Concomitant Chemotherapy and

Radiation Therapy for Advanced StageOropharynx 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



French Trial: Oropharyngeal CA(Denis et al, JCO, 2004)

• Med. Surv. 20 mo 13 mo

• 5 yr LRC 48% 25%

p=.002

• 5 yr DFS 27% 15% p=0.01

• 5 yr OS 22% 16%

p=0.05

Chemo + RT RT Alone



RTOG 0129



RTOG 0129hase III Trial of Concurrent RT and CT for

Advanced Head and Neck Cancer

S

TR

A

T

IF

Y

R

A

ND

O

M

I

Z

E

Zubrod PS

0 or 1

Site : larynx vsnon

Nodal Status :

N0

N1 or N2a-b

N2c-N3

Arm 1 : AFX-CB

72 Gy/42 FXS/6 wks

plus CDDP 100 Mg/M2days 1 and 22

Arm 2 : Concurrent 70 Gy +Cisplatin 100 mg/m2

I.V. on days 1, 22, 43.

IMRT OROPHARYNX



IMRT OROPHARYNXAuthor

Year

n Stage Chemo

%

Median

FU

months

Loco-regional

control

Chao

(Wash U.)

IJROBP 2004

74 76%

III/IV

46% T3/4

27% 33 87%

(4 Yr)

Feng

(Michigan)

JCO 2010

73 III/IV 100% 36 96%

(3 Yr)

De Arruda

(MSKCC)

IJROBP, 2005

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 pharyngealconstrictor/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

P b bilit S ll i P bl



0

. 1

. 2

. 3

. 4

. 5

. 6

0 10 20 30 40 50 60 70 80

Dose superior constrictor muscle (Gy)

Cyberknife (3x + 4x)

Brachytherapy implant

No BT / No Cyberknife

Probability Swallowing Problems

3x4x



Levendag PC, et al. Radiother Oncol . 2007

Dysphagia and Aspiration after Chemoradiotherapy for Head and

N k C Whi h A t i St t A Aff t d d C



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

Neck Cancer: Which Anatomic Structures Are Affected and Can

They Be Spared by IMRT?



Feng JCO 2010

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

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

PEG dependence 1.4% at 1yr



p y

5 pts with strictures 8 pts with

pneumonia — all silent aspirators

• Dysphagia related to dose to PC,Lx, Esoph

• Neck dissection/smoking/t-stage



NEJM 2006

Ph III C225 /RT T i l f



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



RTOG 0522Phase III Trial of Concurrent



RT and CT forAdvanced Head and Neck Cancer

S

T

R

A

T

IF

Y

R

A

ND

O

M

IZ

E

Zubrod PS

0 or 1

Site : larynx vsnon

Nodal Status :

N0

N1 or N2a-b

N2c-N3

Arm 1 : AFX-CB

72 Gy/42 FXS/6 wks

plus CDDP 100 Mg/M2days 1 and 22

Arm 2 : As above + C225

On-Going

TAX 324: Sequential Combined Modality



TherapyTPF vs PF Followed by Chemoradiotherapy

R

A

N

D

O

M

I

ZE

P

P

F

F

Carboplatinum - AUC 1.5Weekly

Daily Radiotherapy

T

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

x3PF: Cis latin 100 + 5-FU 1000 Q 3 weeks x 3

Surgery

as

Needed

Posner NEJM 2007

TAX324 : Survival



Survival Time (months)

S u r v i v a l P

r o b a b i l i t y ( % )

0 6 12 18 24 30 36 42 48 54 60 66 72

0

10

20

30

40

50

60

70

80

90

100

TPF (n=255)

PF (n=246)

Number of patients at risk

TPF:

PF:

255 234 196 176 163 136 105 72 52 45 37 20 11

246 223 169 146 130 107 85 57 36 32 28 10 7

TAX324 : Survival

TPF

62%

PF

48%

Log-Rank P =

0.0058 Hazard

Ratio = 0.70

TPF

67%

PF

54%



H P ill Vi i O h



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



s St at y by V, obacco a d /N Stage

RPA



3yr OS 93% vs 71% vs 46%

D D i ifi i f HPV



Dose Deintensification for HPV+

Oropharynx Cancer

• ECOG 1308: Taxol/Carbo/C225 induction

– IF complete response decrease total dose GTV54Gy+C225

– IF partial response, standard dose 70Gy + C225

• RTOG: Phase III: 70Gy: Cisplatin vs Cetuximab

Cancer of the



Cancer of the

Larynx/Hypopharynx

/Oral Cavity

Kenneth Hu,M.D.Beth Israel Medical Center

NY, NY

CARCINOMA OF THE LARYNXINCIDENCE OF LYMPH NODE METASTASES



Site Incidence

INCIDENCE OF LYMPH NODE METASTASES

Supraglottis

Positive Nodes 55 %

Bilateral Nodes 16 %

Glottis

T1 < 2 %

T2 3-7 %

T3 15-20 %

T4 20-30 %

Subglottis 10-30 %



T1-2NO GlotticTreatment Technique

LOCAL CONTROL OF T1



BY FRACTION SIZE

0

20

40

60

80

100

0 2 4 6 8 10

L o c a l C o n t r o l ( % )

Time from Treatment (Yr.)

≥ 2.25Gy

1.8-1.99 Gy

2.0-2.24 Gy

< 1.8 Gy

94%

92%

81%

79%

P = 0.04

Le IJROBP 1997

LOCAL CONTROL OF T1 LESIONS



BY OVERALL TIME

0

20

40

60

80

100

0 2 4 6 8 10


Time from Treatment Yr.

≤ 43 D

> 50 D

44-50 D

98 %

84%

83%

p = 0.04




BY FRACTION SIZE

0

20

40

60

80

100

0 2 4 6 8 10



≥ 2.25 Gy

2.0-2.24 Gy

1.80-1.99 Gy

< 1.80 Gy




BY OVERALL TIME

0

20

40

60

80

100

0 2 4 6 8 10



≤ 43 D

44-50 D

> 50 D

100%

70%

66%

LOCAL CONTROL FOR T2 GLOTTIC



BY CORD MOBILITY

0

20

40

60

80

100

0 2 4 6 8 10



Normal

Impaired

79%

45%

p = 0.008

LOCAL CONTROL FOR T2 LESIONS



LOCAL CONTROL FOR T2 LESIONS

BY SUBGLOTTIC EXTENSION

0

20

40

60

80

100

0 2 4 6 8 10

L o c a l C o n t r o

l ( % )


Without SGE

With SGE

SGE: Subglottic Extension

77%

58%

p = 0.02

RTOG 95-122006 ASTRO



HYPERFRACTIONATION FOR

T2 VOCAL CORD CAS

T

RA

T

IF

Y

R

A

ND

O

M

I

Z

E

Stage

1. T2a

2. T2b

1. ConventionalFractionation:2 Gy/fx/d to70 Gy/35 fx/7 wks

LC:

2. Hyperfractionation:1.2 Gy/fx BID to79.2 Gy/66 fxs/6.5 wks

Supraglottic Larynx



Supraglottic Larynx

Treatment

Carcinoma of the Supraglottis



1st T1 T2 T3 T4AuthorHarwood 71 68 56 41-52

Wall 89 74 70 46

Mendenhall 100 81 (88) 61 (83) 33 (67)

Wang : Q.D. 74 61 56 29

B.I.D. 84 83 71 84

% Local Contro l w i th Radiotherapy

(and Surg ical Salvage)

R l f Ch th



Role of Chemotherapy

for Larynx/Hypopharynx

Preservation

VA LARYNGEAL CA STUDY



VA LARYNGEAL CA. STUDY

Surgery Radiation Therapy

PR Surgery

CR or PR (3rd Cycle Radiationof Chemo) Therapy

CR InductionChemotherapy(2 Cycles) < PR Surgery Radiation

Induction Chemotherapy: Cisplatin and 5-FU

RAN

DOMI

Z

E



RTOG 91-11 Forastiere NEJM 2003



Phase III Trial to Preserve the Larynx

S

T

RA

T

IF

Y

RA

N

DO

M

IZ

E

Location:

GlotticSupraglottic

T Stage:T2

T3

Early T4N Stage:

N0, N1

N2, N3

Arm 1 : Neoadjuvant CT + RT

CR, PR CP + 5-FURT

X 1 Cycle

CDDP + 5-FU X 2 Cycles

NR Surgery RT

Arm 2 : RT + CDDP

Arm 3 : RT Alone

RTOG 91-11



VA CCRT RT

2 year Laryng-FS 75% 88% 70%

2 year LR control 61% 78% 56%

5 year DM 15% 12% 22%

5-yr. Survival 55% 54% 56%

RTOG 91 11

* Estimated from survival curves

Median F/U 3.8 years



• 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



T1

T2

Stage I

IVb

III

IVa

II



• 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 51mo’s

• 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: 44mo’s

• 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/7wksCalais, G. et al ASCO 2006

Multidisciplinary Head and Neck Symposium, 2010

GORTEC 2000 01:Results



GORTEC 2000-01:Results

• Median F/U 61 mo’s

• 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: Earl Stage Glottic Lar n



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



3F-IMRT 2F-Conventional

R carotid a

D50 8Gy vs 60Gy

IMRT2D

D50: 60Gy

Inferior Constrictor D50 48Gy vs 61.5Gy

D50: 8Gy

IMRT for Advanced Stage Lx/HPX



IMRT for Advanced Stage Lx/HPX

– Studer IJROBP 2011

– Miah IJROBP 2011

– Lee IJROBP 2007

Daly Head and Neck 2011

Toxicity IMRT Larynx/Hypopharynx



Med F/U PEG-d Trach/TL Esoph

Stenosis

Aspiration

Risk

Lee 26mo 26% 3% (gr 5)

Studer 21mo 3% 3%/2%

Daly 30mo 2% 17%

Miah 36mo 5% 17%



T4 N+ Gl tti



T4a N+ Glottic

Supraglottic

Surgery Preferred +Post-OP



Treatment Paradigm



Upfront surgical

resection followed byradiation +/-

chemotherapyIs the preferredtreatment of choice

Oral Cavity Cancer

Post Op Radiation Therapy(PORT)



(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)



p py ( )

• 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 Post-

op

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 vsRadiation: Phase III Trials



RTOG95-01 EORTC22931

# patients 459 334

OPX /OC/ /LX/HPX 42%/27%/21%/10% 30%/26%/22%/20%

% T3-4 61% 66%

% N2-3 94% 57%

% with ECE and/or +margins

59% 70%

RT: %receiving 66Gy 13% 91%

Post-op CT/RT vs RT: Results of



Post op CT/RT vs RT: Results of

EORTC/RTOG Phase III TrialsRTOG95-01 EORTC22931

Median follow up 46mo 60 months

Locoregional failure

Outcomes(CT/RTvs RT)

3yr: 22% vs 33% (p=0.01)

Outcomes(CT/RTvs RT)

5yr: 18%vs 31% (p=0.007)

Disease-free Survival 3yr: 47% vs 36% (p=0.04) 5yr: 47% vs 36% (p=0.04)

Overall Survival 3yr: 56% vs 47% (p=0.09) 5yr: 53% vs 40% (p=0.02)

Distant Metastases 3yr: 20% vs 23% (P=0.46) 5yr: 21% vs 24% (p=0.61)

>Grade 3 acute toxicity 77% vs 34% (p<0.0001) 44% vs 21% (p=0.001)

All late toxicity 21% vs 17% (p=0.29) 38% vs 41% (p=0.25)

RTOG 0234 Ph II R d i d T i l f



RTOG 0234: Phase II Randomized Trial of

Post-op Chemoradiation plus C225 forHigh 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

R lt RTOG 0234



Results: RTOG 0234

CDDP/C225 Taxotere/C225

Locoregional failure 2yr: 21% 2yr: 20%

Disease-free Survival 2yr: 57% 2yr: 66%

Compared to 95-01

(Cddp+RT)

HR 0.85 p=0.19 HR 0.72 p=0.031

Overall Survival 2yr: 69% 2yr: 79%

Distant Metastases 2yr: 26% 2yr: 13%

>Grade 3 acute

heme/derm/mucositis 28%/39%/37% 14%/39%/33%

RTOG 0920:Randomized Study of Post-op RT



y p

+/_ 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



y

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



g

Brachytherapy• Treats limited volumes

• Requires special expertise

• Radiation Exposure to Hospital Personnel (lowdose rate)



Oral Tongue Cancer

Local Control Comparison

R di i S



0

10

20

30

40

50

60

70

80

90

T1 T2 T3

RT (Curie)

Surg (MSKCC)

Radiation vs. Surgery

Decroix Cancer 1981



Conclusion



• Pathologic risk stratification established

• LVI/PNI/Multiple LN without ECE/close marginsrequire RT ? Benefit of C225

• ECE or Positive Margins need addition ofchemotherapy (high dose cddp) to RT

• Brachytherapy should be considered in definitivelytreated oral cavity cancers

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