Management of Advanced Head & Neck Squamous

Cell Carcinoma in The Molecular Era

Mohamed Abdulla (M.D.)Department of Clinical OncologyKasr El-Aini School of Medicine

Cairo UniversityAlexandria, 15/01/09

Squamous cell carcinoma of the head and neck (SCCHN): 98 000 new cases in Europe

annually

SCCHN: mortality in Europe is 43 000

annually

SCCHN accounts for 6% of all malignancies

Worldwide annual incidence of SCCHN:

485 000 new patients; 261 000 deaths

Epidemiology of Epidemiology of SCCHNSCCHN

GLOBOCAN 2002 (http://www-dep.iar.fr)

Challenging Issues:Stages III & IV SCCHN Patients:

2/3 of Patients at Presentation. 5-Year OAS = 30-35%.

20% will develop failures below the clavicles.

Many Modalities of Treatment with Different Sequencing Matters.

Impact of Innovations in Loco-regional Management upon Patient’s Survival.

Treatment Modalities in SCCHN

CTRT alone PalliationRT + CT

Early stage Locally advancedRecurrent and/or metastatic

Refractory

Surgery

Lessons Learned from Meta-Analysis of Chemotherapy Trials

over YearsInvestigat

orNo. of No. of TrialsTrials

No. of No. of PatientPatient

ss

SequencinSequencingg

Survival Survival AdvantaAdvanta

gege

Stell, 1992 28 3977 AllConcurrent

2.8% 7%

Browman, 1994

10 1626 NeoadjuvaNeoadjuvantnt

NegativeNegative

Munro, 1995

54 7443 AllConcurrent

6.5% 12.1%

El-Sayed & Nelson,

1996

25 -- AllConcurrent

4% 8%

Bourhis & Pignon,

1999

-- 10741 AllConcurrent

2.8 – 6.5% 7 – 12.1%

Lessons Learned from Meta-Analysis of Chemotherapy Trials

over Years Cancer Care Ontario Practice Guidelines,

2000: 18 Randomized Controlled Trials. 3192 Patients. Absolute Mortality Risk Reduction with

Concurrent Cth = 11%. Absolute Mortality Risk Reduction with

Monotherapy Platinum Based Cth = 12%. The Cost of Incremental Acute Toxicity.

Lessons Learned from Meta-Analysis of Chemotherapy Trials

over YearsASCO 2004:

87 Trials. 16000 Patients. Survival Advantage:1. All: 5% at 5 y.2. Concurrent: 11% at 5

y.3. Platinum Monotherapy

ASCO 2007

Lessons Learned from Meta-Analysis of Chemotherapy Trials

over Years

Concurrent Chemotherapy Improves Survival by 8-11%.

Platinum Monotherapy is Preferred. Little Role in Pure Neoadjuvant or

Adjuvant Fashions.

Molecular Biology of Head & Neck SCC.

EGF PathwayEGF Pathway EGFR familyEGFR family

EGFR HER2 HER3 HER4

Adapted from:Ciardiello F, et al. N Engl J Med. 2008;358:1160-1174.

Extracellular Domain

Transmembrane Domain

Intracellular Domain

EGF PathwayEGF Pathway EGFR: transmembrane proteinEGFR: transmembrane protein

Tyrosine Kinase Domain

Adapted from:Ciardiello F, et al. N Engl J Med. 2008;358:1160-1174.

EGF PathwayEGF Pathway Receptor specific ligandsReceptor specific ligands

EGFTGFαβ-cellulinHB-EGFEpiregulinAmphiregulin

EGFR HER2 HER3 HER4

NRGsβ-cellulinHB-EGF

NRGs

Adapted from:Ciardiello F, et al. N Engl J Med. 2008;358:1160-1174.

Shc

PI3K

RafMEKK-1

MEKMKK-7

JNKERK

Ras

mTOR

Grb2

AKT

Sos-1

EGFR activation EGFR activation mediates mediates multiple multiple processesprocesses

EGF EGF PathwayPathway

Adapted from:Ciardiello F, et al. N Engl J Med. 2008;358:1160-1174.

ProliferationApoptosis Resistance

Transcription

TGFα Interleukin-8 bFGF VEGF

MetastasisAngiogenesis

Shc

PI3K

RafMEKK-1

MEKMKK-7

JNK ERK

Ras

mTOR

Grb2

AKT

Sos-1

EGF PathwayEGF Pathway

Prognostic & Predictive Importance of EGFR Over expression: > 90% of all HNSCC Patients. Poor Response to ttt with Chemo-

Radiotherapy Through Repopulation of Clonogenic Cells during ttt.

Compromised L.C., DFS, OAS. Associated with Cisplatin-Resistance.

Cetuximab Experience:

Stage III and IV non-metastatic

SCCHN(n=424)

RT (n=213)

ERBITUX + RT (n=211)ERBITUX initial dose (400 mg/m2)1 week before RTERBITUX (250 mg/m2) + RT (weeks 2–8)

ERBITUX + RT in locally advanced SCCHN: Phase III study design

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

aInvestigators’ choice

R

Secondary endpoints: OS, PFS, RR, and safety

Stratified by• KPS• Nodal involvement• Tumor stage• RT regimena

Primary endpoint: Duration of locoregional Control

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

vera

ll S

urv

ival

Treatment Total Death Alive Median

RT 213 130 83 29.3Erbitux + RT 211 110 101 49.0

ERBITUX + RT

RT

ERBITUX + ERBITUX + RTRT RTRT p-p-

valuevalue

5-year OS 5-year OS raterate 46%46% 36%36% 0.020.02

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 J.A, et al. as presented ASTRO 2008

Cetuximab Experience:

Bonner Trial Overview:

Significant Increase in Durability of Locoregional Control (HR = 0.68, P = 0.05).

Better Median Duration for Locoregional Control (24.4 vs 14.9 months).

Significant Reduction in Risk of Death (26%) (HR 0.74, P = 0.03).

Independent Clinical Benefit. No Significant Increase in Grade 3 Co-morbid

Events Apart From Acniform Rash & Fusion Reactions.

No Significant Adverse Affection of Quality of Life.Incorporation of Molecularly Targeted Agents in The Primary Treatment of Squamous Cell Carcinoma of The Head & Neck. Jacques Bernier. Hematol Oncol Clin N Am. 22(2008)1193-1208.

Primary tumor site OropharynxLarynxHypopharynx

Tumor stage T1–T3T4

RT regimen Once dailyTwice dailyConcomitant boost

Overall stage Stage I-III Stage IV

Nodal stageN0N1–N3

KPS 50–8090–100

Gender MaleFemale

EGFR status ≤50% positive>50% positiveUnknown

Age <65 years≥65 years

Forest Plot of the Hazard Ratios by Forest Plot of the Hazard Ratios by Pre-Treatment Characteristics – 5-Pre-Treatment Characteristics – 5-

year Updateyear UpdateSubgroup

0.0 0.6 1.2 1.8Benefit under CTX + ERBITUX Benefit under CTX alone

Bonner J.A, et al. as presented ASTRO 2008

Time (Month)

Pro

babili

ty o

f su

rviv

al

(%)

0 10 20 30 40 50 60 70

1.00

0.75

0.50

0.25

0.00

ERBITUX + RT: Overall Survival by Severity of Acne/Rash

ERBITUX + RT Grade 2-4 Acne/Rash

Bonner J.A, et al. as presented ASTRO 2008

ERBITUX + RT Grade 0-1 Acne/Rash

grade 0–1 grade 2-4

n 81 127

Median 25.6 68.8+

p=0.002

HR (CI)= 0.49 (0.34 – 0.72)

Adverse eventAdverse event RTRT(n=212)(n=212)

ERBITUX ERBITUX + RT + RT

(n=208)(n=208)

p-p-valuevalueaa

Mucositis/stomatitisMucositis/stomatitis 52%52% 56%56% 0.440.44

DysphagiaDysphagia 30%30% 26%26% 0.450.45

Radiation dermatitisRadiation dermatitis 18%18% 23%23% 0.270.27

XerostomiaXerostomia 3%3% 5%5% 0.320.32

Fatigue/malaiseFatigue/malaise 5%5% 4%4% 0.640.64

Acne-like rashAcne-like rash 1%1% 17%17% <0.001<0.001

Infusion-related Infusion-related reactionsreactionsbb 0%0% 3%3% 0.010.01

aFisher’s exact test bListed for its relationship to ERBITUX

ERBITUX + RT: Relevant grade 3–5 adverse events

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

Cetuximab + Rth CRT

• No Phase III Direct Head to Head Comparison.

•Between-Study Comparison of Phase III Studies 20 & 18 months Survival Advantages.

• Discretion of The Treating Physician.

Cetuximab + Rth vs CRT??• Retrospective Analysis at ONE Center.

• 29 Patients (Cetuximab + Rth) vs 103 Patients (CRT).

Caudell JJ, Sawrie SM, Spencer SA, et al. Locoregionally advanced head and neck cancer treated with primary radiotherapy: a comparison of the addition of cetuximab or chemotherapy and the impact of protocol treatment. Int J Radiat Oncol Biol Phys 2008 [E-pub].

Item Cetuximab + Rth

CRT P-Value

3-Y L.C. 71% 75% NS

Distant Metastases FS

92% 87% NS

Disease Specific Survival

79% 77% NS

3-Y OAS 76% 61% 0.02

• Considerable Number of Non-Protocol Patients in CRT Arm.

• Inclusion of Higher Number of T-4 Patients in CRT Arm.

Comparison of overall survival advantage of different combinations

(MACH-NC meta-analyses, Bonner study)

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

Hazard ratio

(95% CI)

CT or Erbitux

effect (p-value)

Absolute benefit

At 2 yearsa

At 5 yearsa

Adjuvant CT+RT1 0.98 (0.85–1.19)

0.74 1% 1%

Neoadjuvant CT +RT1 0.95 (0.88–1.01)

0.10 2% 2%

Concomitant CT + RT1

0.81 (0.76–0.88)

<0.0001 7% 8%

ERBITUX + RT2 0.73 (0.56–0.95)

0.02 7% 10%

aAssuming survival rates of 50% at 2 years and 32% at 5 years in control groups

Bonner J.A, et al. as presented ASTRO 2008

-35%

-30%

-25%

-20%

-15%

-10%

-5%

0%

-35%

-30%

-25%

-20%

-15%

-10%

-5%

0%

Comparison of the reduction in the risk of death (MACH-NC meta-analyses, Bonner

study)

ERBITUX+RT provides a high reduction in the risk of death at 5 years

0%

-5%

-10%

-15%

-20%

-25%

-30%

Adjuvant CT+RT1

ERBITUX +RT2

-2%-5%

-19%

-27%

1) Pignon JP, et al. Lancet 2000;355:949–955

2) Bonner J.A, et al. ASTRO 2008

Neoadjuvant CT+RT1

Concomitant CT+RT1

Cetuximab + CRT in Phase III Trials in Advanced HNSCC:

Radiation Therapy Oncology Group:Cisplatin-Based CRT +/- Cetuximab.

Groupe Oncologie Radiotherapie Tet et Cou:Rth + Cetuximab vs Cetuximab + Carboplatin/5-Fu-Based CRT.

Pfister DG, Su YB, Kraus DH, et al. Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: a pilot phase III study of a new combined-modality paradigm. J Clin Oncol 2006;24(7):1072–8

Other Epidermal Growth Factor Receptor-Targeted Monoclonal Antibodies Phase I/II: Panitumumab (Vectibix). Zalutumumab (Humax-EGFr). Nimotuzumab (Theraloc).

Epidermal Growth Factor Tyrosin Kinase Inhibitors Phase I/II Trials:

Gefitinib (Iressa) + Cisplatin + Accelerated Rth: CR in 52% (46 Patients).

Erlotinib (Tarceva) + Cisplatin-Based CRT: CR in 84% (25 Patients).

VEGF Inhibitor, Bevacizumab (Avastin):

Phase I/II trials. Significant Morbidity included; Fistula Formation

(11%) & Ulceration/Tissue Necrosis (9%).

Agents Directed at Multiple Molecular Targets:

Lapatinib (Tycerb): Phase II Trial; Cisplatin-Based CRT +/- Lapatinib.

Vandetanib (Zactema): Phase II Vandetanib and Docetaxel in Locally Advanced HNSCC not amenable to Surgery or Rth.