Multimodular treatment in

Head and Neck Squamous Cell

Carcinoma (HNSCC)

Amanda Psyrri, MD,FACPAttikon University Hospital

Athens, Greece

Learning objectives

After reading and reviewing this material, the participant should

be able to:

Evaluate the role of induction, definitive concurrent chemotherapy

and sequential therapy in locally advanced HNSCC

Describe organ preservation strategies

Discuss the common indications for postoperative chemoradiation

Define the role of bioradiotherapy with cetuximab

Understand HPV-associated oropharyngeal cancers

Outline

Introduction

Concurrent chemoradiotherapy

Induction chemotherapy

Sequential therapy

Bioradiotherapy with cetuximab

HPV-associated oropharyngeal cancers

Surgical management of the neck

Many subsites

Heterogeneous group of tumours of varying primary sites

95% are HNSCC

Oral cavity

Oropharynx/hypopharynx

Larynx

Nasopharynx

Other anatomic sites

Paranasal sinuses

Salivary glands

Lip

Image courtesy of Massachusetts General Hospital Cancer Center

Etiology

Traditionally, tobacco and alcohol use account for the majority

of HNSCC

A growing proportion of oropharyngeal squamous cell carcinomas

is caused by high-risk Human Papillomaviruses (HPV),

especially HPV16

Incidence in the USA

In 2015, 45,780 new cases of oral cavity and pharynx cancer and

8,650 deaths are expected to occur in the United States

Oral cavity and pharynx

All races

White

Black

Stage distribution by raceUnited States 2004–2010

5-year relative survival rates

by race and stageUnited States 2004–2010

20

40

60

80

100

0Localised Regional Distant

31 32

20

47 47 49

18 1627

20

40

60

80

100

0Localised Regional Distant

83 8377

61 62

4237 38

24

All stages

63 64

44

Redrawn from Siegel MPH, et al. CA Cancer J Clin 2015;65:5–29

Incidence and Mortality Worldwide

1. Ferlay J, et al. GLOBOCAN 2012 v1.0. Available from: http://globocan.iarc.fr, accessed December 2013

2. Ferlay J, et al. Eur J Cancer 2013;49:1374–1403

15th most common

cancer in Europe1

• Lip and oral cavity cancer in Europe

(2012):

• 61,400 new cases diagnosed (2% total)

• ~34,100 cases of other pharyngeal cancer

diagnosed (1% total cancer cases)1

• Highest World age-standardised incidence

rates in Hungary (both men and women);

lowest rates in Greece for men and

Cyprus for women

• Worldwide (2012):

• >142,000 cases of other pharyngeal

cancer diagnosed (1% total cancer cases)

• Lip and oral cavity cancer incidence rates

highest in Melanesia and lowest in

Western Africa, partly reflecting varying

data quality worldwide

• Incidence rates of other pharyngeal

cancer highest in Western Europe and

lowest in Western Africa1

WHO Europe region (adults)

Estimated numbers (x100)

Epidemic of HPV-associated OPC*

Incidence rates for overall oropharyngeal

cancer, HPV-positive oropharyngeal cancer,

and HPV-negative oropharyngeal cancer from

1988 to 2004 in Hawaii, Iowa, and Los Angeles

Estimated age-standardised incidence of human

papillomavirus (HPV)-positive and HPV-negative

tonsillar cancer squamous cell carcinoma cases

per 100,000 person-years, Stockholm, Sweden,

1970-2006

Chaturvedi AK, et al. J Clin Oncol 2011;29:4294–301.

Reprinted with permission. © 2011 American Society of

Clinical Oncology. All rights reserved

Error bars indicate 95% CI.

Näsman A, et al. Int J Cancer 2009;125:362–6. Reproduced with

permission from Wiley

Staging overview

T and N stages vary by anatomic site

≥N2 or T4 tumours locoregionally advanced (Stage IV)

Typically T1: ≤2 cm, T2: 2-4 cm, T3: ≥4 cm, T4: invades adj. structures

N1: single LN ≤3 cm, N2: LN ≥2 cm or several LN, N3: >6 cm

TNM: tumour nodes metastases

Stage TNM

Stage 0 TisN0M0

Stage I T1N0M0

Stage II T2N0M0

Stage III T3N0, T1-3N1, M0

Stage IVA T4a N0-2,M0, T1-3N2,M0

Stage IVB

Stage IVC

Any T, N3, M0, T4b, Any N, M0

M1, any T or N

Patel SG, et al. CA Cancer J Clin 2005;55;242-258

HNC, head and neck cancer; MACH-NC, meta-analysis of chemotherapy in head and neck cancer; SCC, squamous cell

carcinoma; ORR, overall risk reduction; RR, relative risk.

Pignon JP, et al. Lancet 2000;355:949-955

Trials N RR P valueAbsolute benefit

(5 Yrs), %

Adjuvant 8 1854 0.98 NS 1

Induction 31 5245 0.95 NS 2

Concomitant 26 3727 0.81 < 0.0001 8

Meta-analysis of chemotherapy in HNC

(MACH-NC)

63 randomised trials (1965-1993)

n = 10,717 pts with SCC of the oropharynx, oral cavity, larynx, or

hypopharynx

Comparison of locoregional treatment with and without

chemotherapy

Median follow-up: 6 years

Overall benefit 4% at 5 years (32% vs. 36%)

MACH-NC, meta-analysis of chemotherapy in head and neck cancer; IC: induction chemotherapy

Pignon JP, et al. Radiother Oncol 2009;92:4-14

MACH-NC: An Update

24 added trials–87 studies, 16,485 patients

MACH-HN I: 8% absolute benefit concurrent-no significant effect

of IC

No significant difference (p = 0.19) was seen between

mono-chemotherapy (HR 0.84) and poly-chemotherapy (HR 0.78)

In the mono-chemotherapy group, the effect of chemotherapy was

significantly higher (p = 0.006) with platin than with other types of

mono-chemotherapies

Age matters

Younger than 50 years of age: 24% increased survival

Older than 70 years of age: 3% increased survival

Pluses and minuses of chemoradiation

Improves locoregional control

Facilitates organ preservation

Beneficial impact on survival

Doubles the rate of severe acute mucositis

Use may be excessive based on stage

Long-term functional deficits in speech, swallowing, mobility

Study Eligibility N

T + PF

CR/PR,

n/N (%)

PF

CR/PR,

n/N (%)

TPF/PF

PFS, Mos

TPF/PF OS,

Mos

P Value

(HR)

Hitt

JCO 2005Stage III-IV

38

2

33/47

(80)

14/54

(68)

20

12

43

37

2 yrs:

66%/61%

.035

(0.67)

TAX 323

NEJM 2007Unresectable

35

8(68) (54)

11

8

18.6

14.2

3 yrs:

24%/18%

.005

(0.71)

Gortec

ASCO 2006

L/HP

II-IV

20

5

43/39

(82)

30/30

(60)

LP:

63%/41%.036

TAX 324

NEJM 2007III-IV

50

1

17/55

(72)

15/49

(64)

2-yr PFS:

53%/42%

70

30

3 yrs:

62%/48%

.006

(0.7)

CR, complete response; HP, hypopharynx; HR, hazard ratio; L, larynx; LP, larynx preservation; OS, overall survival;

PF, cisplatin, 5-fluorouracil; PFS, progression-free survival; PR, partial response; T, docetaxel;

TPF, docetaxel, cisplatin, 5-fluorouracil.

Randomised trials of induction

PF ± taxane

Trial Eligibility Target N*Control

TxExp Tx OS

DeCIDE

U ChicagoN2-3

400

285DHFX

TPF x 2

DHFXNS

Paradigm

DFCIStages III-IV

300

145

Cisplatin

CB-RT

TPF x 3

Carbo-RT or

D-CB-RT

NS

SWOG Oropharynx 400Cisplatin

RT

TPF x 1-3

surgery or

cisplatin-RT

*All powered to show survival difference of 10% to 15%.

Carbo, carboplatin; CB, concomitant boost; chemoRT, chemoradiation therapy; DFCI, Dana-Farber Cancer Institute;

RT, radiation therapy; TPF, docetaxel, cisplatin, 5-fluorouracil. DHFX, docetaxel, fluorouracil, and hydroxyurea

Randomised trials of sequential therapy*:

Definitive chemo RT ± induction

Psyrri A, Presented at ASCO 2013 Lecture: EGFR, new data and best use of inhibitors (adapted from

http://www.slideshare.net/melodyhsiao/scchn-cancer-report

1. Psyrri A, et al. Clin Can Res 2005;11:5856-62; 2. Baumann M, Krause M. Radiother Oncol 2004;72:257‒266;

3.Ang KK, et al. Cancer Res 2002;62:7350–7356

EGFR as a molecular target in HNSCC

EGFR expression linked to poorer outcome1 and reduced response

to radiotherapy2,3

*ADCC: antibody dependent cellular cytotoxicity

EGFR, epidermal growth factor receptor; mAb

Li S, et al. Cancer Cell 2005;7:301–311

Figure courtesy of Psyrri A. Presented at ASCO 2013; adapted from Vermorken JB, MCO 2011; ESO-ESMO Masterclass in

Clinical Oncology www.slideshare.net

Cetuximab

Cetuximab

IgG1 mAb

Chimeric protein

Specifically binds with high affinity

to FcγRI (EC50 = 0.13 nM) and

FcγRIIIa (EC50 = 6 nM)

Induces apoptosis and ADCC*

Preclinical synergistic activity in

combination with chemotherapy

and radiotherapy

Arm 2 (RT + C)

Radiation therapy +

cetuximab wkly

R

A

N

D

O

M

I

S

E

Arm 1 (RT)

Radiation therapy

Bonner JA, et al. N Engl J Med 2006;354:567-578

Eligibility

Patients with locoregionally

advanced squamous cell

carcinoma of either the oropharynx,

hypopharynx, or larynx

Primary endpoints:

Overall survival,

locoregional control

Phase III Study Design

Stratified by

Karnofsky score: 90-100 vs. 60-80

Regional nodes: Negative vs. positive

Tumour stage: AJCC T1-3 vs. T4

RT fractionation: Concomitant

boost vs. once daily vs. twice

daily

Toxicity, %

RT (n = 212) RT + C (n = 208)

All Grades Grades 3/4 All GradesGrades

3/4

Skin reaction 91 18 97† 34‡

Mucositis/stomatitis 93 52 91 54

Dysphagia 63 30 64 25

Xerostomia 70 3 64 4

Fatigue/malaise 50 5 52 4

Infusion reaction* -- – 14‡ 3†

*Listed for its relationship to cetuximab; †P < 0.05; ‡P < 0.001, Fisher’s exact test.

Bonner JA, et al. N Engl J Med 2006;354:567-578

Most common adverse events

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 10 20 30 40 50 60 70

Months

Pro

babili

ty o

f o

ve

rall

su

rviv

al

ERBITUX + RT

RT

ERBITUX + RT RT p-value

5-year OS rate 46% 36% 0.02

p = 0.02

ERBITUX + RT improves significantly long term survival,

with nearly half of the patients alive at 5 years

HR=0.73 (0.56–0.95)

Bonner JA, et al. Lancet Oncol 2010;1:21–28. Reprinted from The Lancet, Copyright (2010). With permission from Elsevier

Treatment Total Dead Alive Median

Erbitux + RT 211 110 101 49.0

RT 213 130 83 29.3

ERBITUX + RT: Overall survival

5 year update

Forastiere AA, et al. N Engl J Med 2003;349:2091-2098

R

A

N

D

O

M

I

S

E

Location

1. Glottic

2. SupraglotticS

T

R

A

T

I

F

Y

T Stage

1. T2

2. T3, fixed cord

3. T3, no cord fixation

4. T4, with base of tongue ≤ 1 cm

N Stage

1. N0, N1

2. N2, N3

Chemotherapy

Arm 1: cisplatin 100 mg/m2/5-FU 1 gm/m2/24 hrs CVI x 120o q3wks x 3

Arm 2: cisplatin 100 mg/m2 Days 1, 22, 43 of RT

Arm 1:

Arm 2:

Arm 3:

CR, PR x 3 d cycle RT

CDDP/5-FU

x 2 cycles

NR surgery RT

Radiation therapy + CDDP

Radiation therapy

RTOG 9111: Larynx Preservation Trial

Phase III larynx preservation trial: induction chemotherapy and radiation

therapy vs. concomitant chemotherapy and radiation therapy vs. radiation

therapy alone

5-FU, 5-fluorouracil; cDDP, cisplatin; DFS, disease-free survival; DMFS, distant metastasis-free survival; FS, free survival;

KPS, Karnofsky performance score; LFS, laryngectomy-free survival; OS, overall survival; RT, radiation therapy;

SGL, supraglottal larynx; SS, statistically significant.

Forastiere AA, et al. N Engl J Med 2003;349:2091-2098

Arm cDDP/5-FU RT RT/cDDP RT

Enrolled, n (evaluable) 180 (173) 182 (172) 185 (173)

2-yr laryngectomy FS, % 59 66 53

5-yr DMFS, % 85 88 78

5-yr DFS, % 38 36 27

5-yr OS,% 55 54 56

RTOG 9111: Larynx Preservation Trial

The median follow-up among surviving patients, 3.8 years

Demographics: median age 59 years; 94% KPS 80; 50% N0; 68% SGL;

28% N2-3

Conclusions

RT/cDDP: stat signif in LFS (P = 0.01)

No SS diff in survival

Forastiere AA, et al. J Clin Oncol 2013;31:845-852. Reprinted with permission. ©2013 American Society of Clinical Oncology. All rights reserved

P<0.001

P=0.53 P=0.0015

P=0.02

(A) Laryngeal preservation, (B) laryngectomy-free survival, (C)

overall survival, and (D) locoregional control according to

treatment group; conc., concomitant; ind., induction; RT,

radiation therapy

P=0.03

Survival, limited to (A) deaths from study cancer and (B) deaths

not caused by study cancer according to treatment group;

conc., concomitant; ind., induction; RT, radiation therapy

Forastiere AA, et al. J Clin Oncol 2013;31:845-852. Reprinted with permission. ©2013 American Society of Clinical Oncology. All rights reserved

5-FU, 5-fluorouracil; CI, confidence interval; HR, hazard ratio; RT, radiation therapy; SCCHN, squamous cell carcinoma of the

head and neck; TPF, docetaxel, cisplatin, 5-fluorouracil; Ctx: chemotherapy

1. Pignon JP, et al. Lancet 2000;355:949-955; 2. Bonner JA, et al. Lancet Oncol 2009;11:21-8;

3. Vermorken JB, et al. N Engl J Med. 2007;357:1695-1704; 4. Posner MR, et al. N Engl J Med 2007;357:1705-1715.

Nonsurgical treatment options for locally

advanced HNSCC

Trial RT (Gy)F/U,

mosLRC, % DFS, % OS, %

RTOG 9501[1]

≥ 2 LN, ECE, +

margins

n = 459

(60-66)46

81 vs. 70

(P = 0.01)

33 vs. 25

(P = 0.04)

45 vs. 38

(P = 0.19)

EORTC 22931[2]

N2-3, ECE, +

margins

n = 350

(66)60

82 vs. 69

(P = 0.007)

47 vs. 36

(P = 0.04)

53 vs. 40

(P = 0.002)

Bachaud[3]

+ ECE

n = 83

(> 60) 60

70 vs. 55

(P = 0.05)

45 vs. 23

(P < 0.02)

36 vs. 13

(P < 0.01)

1. Cooper JS, et al. N Engl J Med. 2004;350:1937-1944; 2. Bernier J, et al. N Engl J Med. 2004;350:1945-1952;

3. Bachaud JM, et al. Int J Radiat Oncol Biol Phys. 1991;20:243-246.

DDP, cisplatin; CT, chemotherapy; DFS, disease-free survival; ECE, extracapsular extension; F/U, follow-up;

LN, lymph node; LRC, locoregional control; OS, overall survival; RT, radiation therapy;

HNSSC, head and neck squamous cell carcinoma

Adjuvant Trials: HNSCC RT ± CT (DDP)

Adapted from Bernier J, et al. Head and Neck Volume 27 Issue 5 Oct 2005

EORTC versus RTOG eligibility

Stage III-IV

OP, Ocw

Level 4 or 5

pos. nodes

Perineural

Disease

Vascular

Embolisms

EORTC

2+ pos. nodes

RTOG

Margins+

ECE

Separate trials are currently designed for

intermediate-risk and high-risk groups

Cooper JS, et al. N Engl J Med 2004;350:1937-1944; Bernier J, et al. N Engl J Med 2004;350:1945-1952;

Ang KK, et al. Int J Radiat Oncol Biol Phys 2001;51:571-578

Risk stratification

Category Standard of care

Favourable None

Low 56-60 Gy

Intermediate (ECE-/margin-) 60-66 Gy

High (ECE+/margin+) 60-66 Gy + cisplatin

Refining adjuvant therapy

CRT: chemoradiotherapy; OS: overall survival

Strategies to improve outcomes in

HNSCC utilising EGFR inhibitors

Treatment intensification of locally advanced HNSCC to improve OS

Randomised trials: CRT+EGFR inhibitor versus CRT

EGFR inhibition in the post-induction setting to reduce toxicity in

sequential design

Randomised phase II studies of induction chemotherapy followed by

either chemoradiotherapy or cetuximab radiotherapy to reduce toxicity

without compromising efficacy

Author # pts Treatment ComparatorPrimary

endpointSetting S vs. E

P

value

Giralt et al.

2012150 C+EBRT+P C+ EBRT 2 yr LRC

Locally

advanced

68%

vs.

61%

0.3

Martins et al.

2013204

C+RT+

Erlotinib

C+RTCRR

Locally

advanced

40%

vs.

52%

0.08

Ang et al.

2011895

C+RT+

cetuximabC+RT PFS

Locally

advanced

64%

vs.

63%

NS

C: cisplatin; EBRT: external beam radiation therapy; RT: radiation therapy; S: standard, E: experimental arm; P: Panitumumab;

CRR: complete response rate

Randomised trials of EGFR inhibitor plus

chemoradiation in HNSCC

Toxicity Grade ≥3

AuthorMucositis Skin reactions

Skin reactions

out of field

E S E S E S

Ang 43% 33% 25% 15% 29% 1%

Giralt 11% 5% 28% 13% 11% 0%

Martins 48% 48% 13% 2% NR NR

EGFR inhibitor + chemoradiation: Toxicity

CRT: chemoradiotherapy; OS: overall survival

Strategies to improve outcomes in

HNSCC utilising EGFR inhibitors

Treatment intensification of locally advanced HNSCC to improve OS

Randomised trials: CRT+EGFR inhibitor versus CRT

EGFR inhibition in the post-induction setting to reduce toxicity in

sequential design

Randomised phase II studies of induction chemotherapy followed by

either chemoradiotherapy or cetuximab radiotherapy to reduce toxicity

without compromising efficacy

TPF (153 patients)

3 cycles, 1 cycle q3w

T = 75 mg/m² on day 1

P = 75 mg/m² on day 1

F = 750 mg/m² on day 1 to 5

60 patients: RT 70 Gy

Cisplatin 100 mg/m² on days 1, 22 and 43

56 patients: RT 70 Gy

ERBITUX 400 mg/m² 1 wk prior to RT

then 250 mg/m² weekly on wks 1 to 7

R

Total laryngectomy

+ post-op RT

< PR

23

≥ PR

116

P: cisplatin; F: 5-fluorouracil; T: docetaxel; TL: total laryngectomy; PR: partial response ; RT: radiotherapy;

CT: computed tomography; Tx: treatment

Lefebvre JL, et al. J Clin Oncol 2013;31:853-859

The randomised Phase II Study:

TREMPLIN

Previously untreated SCC larynx/hypopharynx suitable for TL

Primary endpoint: Larynx preservation 3 months after treatment

Secondary endpoints: Larynx function preservation and survival

18 months after treatment

Cisplatin

n = 58

ERBITUX

n = 56p-value

Grade 3 mucositis

Grade 4 mucositis

25 (43%)

2

24 (43%)

1NS

Grade 3 in field skin toxicity

Grade 4 in field skin toxicity

14 (24%)

1

29 (52%)

3

< 0.001

Other toxicities, any grade,

justifying a protocol

modification

Renal toxicity

Hematological toxicity

Poor general condition

Infusion-related reaction

9 (15.5%)

8 (14.0%)

7 (12.0%)

0

0

0

1 (1.7%)

3 (5.0%)

Protocol modification due to

acute toxicity33 (57%) 19 (29%) 0.02

Lefebvre JL, et al. J Clin Oncol 2013;31:853-859

Acute toxicity during RT

*2 patients did not start the treatment in the cisplatin arm

At 18 months after end

of treatment

Last evaluation with a median

follow-up of 36 months

Cisplatin ERBITUX p-value Cisplatin ERBITUX p-value

Total of local (+/- regional)

failures5 (8.3%) 8 (14.3%)

Log-rank:

0.307 (11.7%)

12

(21.4%)

Log-rank:

0.14

Feasible salvage

total laryngectomy0/4* 7/8 0.01 1/6*

9/12(1 refused)

0.04

Successful salvage

total laryngectomy0/1 7/8

Ultimate local failure rate 6 (10%)* 5 (8.9%) NS

Regional failure alone 5 (8.3%) 5 (8.9%) NS 5 (8.3%) 5 (8.9%) NS

Distant metastases 2 (3.3%) 2 (3.6%) NS

Second primary tumour 3 (5.0%) 3 (5.3%) NS

*Data missing for 1 patient lost to follow-up at 5 months

ITT: intention to treat

Lefebvre JL, et al. J Clin Oncol 2013;31:853-859

Carcinologic events (ITT)

Primary endpoint

(3 months after end of Tx)Cisplatin

n = 60

ERBITUXn = 56

p-value

Larynx preservation, n (%)

(larynx in place without tumour)57 (95%) 52 (93%) 0.63

Secondary endpoints

(18 months after end of Tx)Cisplatin

n = 60

ERBITUXn = 56

p-value

Larynx function preservation, n (%)

(larynx in place without

tumour/trach/feeding tube)

NB: At 18 months or at death

52 (87%) 46 (82%) 0.68

Overall survival

NB: Since randomisation92 % 89 % Log-rank: 0.44

Endpoints (ITT)

NB: 1 pt lost to FU in the Cisplatin arm is considered as failure

Lefebvre JL, et al. J Clin Oncol 2013;31:853-859

With permission of Maria Ghi, et al. ASCO 2012, abstract 5513

A phase II/III study comparing CRT to

cetuximab/RT with or without induction

TPF in locally advanced HNSCC

CT/RT

(n=215)%

RT/cetuximab

(n=133)%

p value

Skin rash any grade

Grade 3-4

5

1

55

8

<0.01

<0.01

Nausea any grade

Grade 3-4

23

0

10

0

<0.01

Vomiting any grade

Grade 3-4

11

0

7

0

0.22

Renal any grade

Grade 3-4

3

0

0

0

0.05

Neurological any grade

Grade 3-4

4

1

2

1

0.33

0.58

Neutropenia

Grade 3-4

5

3

2

1

0.08

0.19

Febrile neutropenia 4 0 0.04

Mucositis any grade

Grade 3

Grade 4

78

37

4

76

35

2

0.63

0.79

0.45

In-field skin toxicity any grade

Grade 3

Grade 4

59

13

1

69

20

1

0.05

0.07

0.58

Maria Ghi, et al. ASCO 2012, abstract 5513

HPV+,p16+

p16-

Weinberger PM, et al. J Clin Oncol 2006;24:736–47.

Reprinted with permission. © 2006 American Society

of Clinical Oncology. All rights reserved

Oropharyngeal cancer disease variants:

tobacco-related, HPV-related and mixed

Forastiere A, et al. N Engl J Med 2001;345:1890-1900;

Koontongkaew S. J Cancer 2013;4:66-83. Available from http://www.jcancer.org/v04p0066.htm. CC BY-NC-ND 3.0

HPV and survival

The relative survival for HPV positive patient is independent of

therapy as long as this therapy is within the current standard of care

Risk of death is consistently less than 60% that of HPV negative

cancers across studies

The absolute survival difference is consistently higher than 30%

Adapted from: Ang KK, et al. N Engl J Med 2010;363:24–35

Oropharynx: Classification of patients

into risk-of-death categories

>10 pack-years

(n=65)

≤10 pack-years

(n=23)

>10 pack-years

(n=90)

≤10 pack-years

(n=88)

N0-N2a

(n=26)

N2b-N3

(n=64)

T2-T3

(n=15)

T4

(n=8)

42.9% at low risk

3 year OS = 93.0%

27.4% at high risk

3 year OS = 46.2%

29.7% at intermediate risk

3 year OS = 70.8%

HPV-positive

(n=178)

HPV-negative

(n=88)

Oropharyngeal cancer

(n=266)

Huang SH, et al. J Clin Oncol 2015;33:836–45. Reprinted with permission. © 2015 American Society of Clinical Oncology. All rights reserved

OS by UICC/AJCC TNM Stage

(7th edition)

Prognostic

Grouping

Model of

HPV(+) OPC

M1 disease considered Group IVB

Too few cases to analyse; policies too varied

Huang SH, et al. J Clin Oncol 2015;33:836–45. Reprinted with permission. © 2015 American Society of Clinical Oncology. All rights reserved.

Treatment deintensification

Aims to reduce treatment-related morbidity and improve patient

quality of life without compromising treatment effectiveness

Patients with HPV+ OPSCC are younger and expected to live long;

therefore, morbidity resulting from late toxicity is a concern in these

patients

Deintensification strategies include: administering radiotherapy

alone, reducing the dose of radiotherapy and substituting

chemotherapy with cetuximab

Stage III/IV

Oropharynx

p16+R

A

N

D

O

M

I

S

E

II: Accelerated IMRT

70 Gy/6 weeks (cetuximabx8)

I: Accelerated IMRT 70 Gy/6 weeks

(cisplatin 100 mg/m², d1, 22)

Stratification factors: cN-stage (cN0-2a vs. cN2b- cN3), cT-stage (T1-2 vs.T3-4)

Zuprod Performance Status (0 vs. 1), smoking history (<10py vs. >10py)

Radiation therapy oncology group 1016 :

Study Design

Cmelak A, et al. ASCO 2014

Cisplatin 75/m2 d1

Paclitaxel 90/m2 d1, 8, 15

Cetuximab 250/m2 d1, 8, 15

Q 21 days for 3 cycles

CLINICAL CR

Low dose IMRT 54 Gy /

27 fx* + Cetuximab qWeek

CLINICAL PR/SD

Full dose IMRT 69.3 Gy /

33 fx* + Cetuximab qWeek

Induction

chemotherapy

Concurrent

chemoradiation

IMRT margins for primary: 1.0 to 1.5 cm around gross disease

Nodal margin: 1 cm margin minimum, treat entire nodal level

Primary Objective: 2-year PFS after low-dose IMRT (stat aim: 2-year 85% or better)

Eligibility

OPSCC

resectable

HPV ISH +

and / or p16+

Stage III, IVA

IMRT: intensity modulated radiation therapy

Cmelak A, et al. ASCO 2014

ECOG 1308: Phase II Schema

R

E

S

P

O

N

S

E

E

V

A

L

U

A

T

I

O

N

Cohort (n) 2 year PFS (90% CI) 2 year OS (90% CI)

All low dose pts (62) 0.80 (0.70, 0.88) 0.93 (0.85, 0.97)

T4a (7) 0.54 (0.19, 0.79) 0.86 (0.45, 0.97)

Non-T4a (55) 0.84 (0.73, 0.91) 0.94 (0.86, 0.98)

N2c (19) 0.77 (0.56, 0.89) 0.95 (0.76, 0.99)

Non-N2c (43) 0.82 (0.69, 0.90) 0.93 (0.82, 0.97)

Smoker >10 pk-yrs (22) 0.57 (0.35, 0.73) 0.86 (0.67, 0.94)

Smoker ≤10 pk-yrs (40) 0.92 (0.81, 0.97) 0.97 (0.87, 0.995)

Smoker ≤10 pk-yrs, <T4,

N2c (27)0.96 (0.82, 0.99) 0.96 (0.82, 0.99)

All high-dose pts (15)* 0.65 (0.41, 0.82) 0.87 (0.63. 0.96)

*3 high-dose pts did not go on to receive RT

Cmelak A, et al. ASCO 2014

Endpoint: 2yr PFS and OS

Neck dissection

Always: Patients who have any clinically apparent residual disease

after chemoradiotherapy

If surgical salvage is necessary for the primary tumour, a neck

dissection may be required to access the primary or for donor

vessels for free flap reconstruction

Observation is acceptable if: No lymph node or lymph node <1 cm at

CT/MRI and negative PET/CT after chemoradiotherapy

Conclusions

Cisplatin chemoradiotherapy remains the standard of care for locally

advanced (LA) HNSCC

Cetuximab is approved with radiation for LA-HNSCC but no

prospective comparison with cisplatin-RT has been performed

TPF is the preferred induction regimen

Sequential therapy is not superior to chemoradiotherapy alone

HPV-positive patients constitute a separate prognostic and

therapeutic cohort

Deintensification trials for HPV-associated oropharyngeal cancers

are ongoing

Thank you!