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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.