1. Management of Advanced Head & Neck Squamous Cell Carcinoma in The Molecular Era
Mohamed Abdulla (M.D.)
Department of Clinical Oncology
Kasr El-Aini School of Medicine
Cairo University
Alexandria, 15/01/09

2. Epidemiology of SCCHN
Squamous cell carcinoma of the head and neck (SCCHN): new cases in Europe annually
SCCHN: mortality in Europe is annually
SCCHN accounts for 6% of all malignancies
Worldwide annual incidence of SCCHN: new patients; deaths
GLOBOCAN 2002 (

3. 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.

4. Treatment Modalities in SCCHN
Early stage Locally advanced
Recurrent and/or metastatic
Refractory
RT alone CT
Palliation
RT + CT
Surgery

5. Lessons Learned from Meta-Analysis of Chemotherapy Trials over Years
Investigator
No. of Trials
No. of Patients
Sequencing
Survival Advantage
Stell, 1992 28
3977
All
Concurrent
2.8% 7%
Browman, 1994 10
1626
Neoadjuvant
Negative
Munro, 1995 54
7443
6.5%
12.1%
El-Sayed & Nelson, 1996 25 -- 4% 8%
Bourhis & Pignon, 1999
10741
2.8 – 6.5%
7 – 12.1%

6. 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.

7. Lessons Learned from Meta-Analysis of Chemotherapy Trials over Years
ASCO 2004:
87 Trials.
16000 Patients.
Survival Advantage:
All: 5% at 5 y.
Concurrent: 11% at 5 y.
Platinum Monotherapy
ASCO 2007

8. 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.

9. Molecular Biology of Head & Neck SCC.

11. EGF Pathway EGFR family EGFR HER2 HER3 HER4 Adapted from:
The ErbB family of Proteins comprises 4 structurally related receptor tyrosin kinases
EGFR
HER2
HER3
HER4
Adapted from:
Ciardiello F, et al. N Engl J Med. 2008;358:

12. Tyrosine Kinase Domain
EGF Pathway
EGFR: transmembrane protein
Extracellular Domain
Transmembrane Domain
Intracellular Domain
Tyrosine Kinase Domain
Adapted from:
Ciardiello F, et al. N Engl J Med. 2008;358:

13. EGF Pathway Receptor specific ligands NRGs β-cellulin HB-EGF
EGF TGFα β-cellulin HB-EGF Epiregulin Amphiregulin
NRGs
And about 13 polypeptide extracellular ligands
EGFR
HER2
HER3
HER4
Adapted from:
Ciardiello F, et al. N Engl J Med. 2008;358:

14. EGF Pathway EGFR activation mediates multiple processes Shc PI3K Grb2
AKT
Sos-1
Ras
mTOR
Raf
MEKK-1
MEK
MKK-7
JNK
ERK
Adapted from:
Ciardiello F, et al. N Engl J Med. 2008;358:

15. TGFα Interleukin-8 bFGF VEGF
EGF Pathway
Metastasis
Angiogenesis
Shc
PI3K
Raf
MEKK-1
MEK
MKK-7
JNK
ERK
Ras
mTOR
Grb2
AKT
Sos-1
TGFα Interleukin-8 bFGF VEGF
Proliferation
Apoptosis Resistance
Transcription

16. 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.

18. Cetuximab Experience:
ERBITUX + RT in locally advanced SCCHN: Phase III study design
RT (n=213)
Stage III and IV non-metastatic SCCHN
(n=424) R
ERBITUX + RT (n=211)
ERBITUX initial dose (400 mg/m2) 1 week before RT
ERBITUX (250 mg/m2) + RT (weeks 2–8)
Stratified by
KPS
Nodal involvement
Tumor stage
RT regimena
To date the only targeted therapy that has demonstrated significant improvement in the outcome of patients with locally advanced HNSCC patients compared with standard therapy alone in a controlled phase III is the EGFR targeting monoclonal antibody Cetuximab (Erbitox)
Primary endpoint: Duration of locoregional Control
Secondary endpoints: OS, PFS, RR, and safety
aInvestigators’ choice
Bonner J, et al. N Engl J Med 2006;354:567–578

19. Cetuximab Experience:
ERBITUX + RT improves significantly long term survival, with nearly half of the patients alive at 5 years
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
ERBITUX + RT RT
p-value
5-year OS rate
46%
36%
0.02
ERBITUX + RT
Probability of Overall Survival RT
HR=0.73 (0.56–0.95)
p = 0.02
Months
Treatment Total Death Alive Median
Erbitux + RT RT
Bonner J.A, et al. as presented ASTRO 2008

20. 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)

21. Benefit under CTX + ERBITUX
Forest Plot of the Hazard Ratios by Pre-Treatment Characteristics – 5-year Update
Subgroup
Primary tumor site Oropharynx Larynx Hypopharynx Tumor stage T1–T3 T4
RT regimen Once daily Twice daily Concomitant boost Overall stage Stage I-III Stage IV Nodal stage N0 N1–N3
KPS 50–80 90–100
Gender Male Female
EGFR status ≤50% positive >50% positive Unknown
Age <65 years ≥65 years
0.0
0.6
1.2
1.8
Benefit under CTX + ERBITUX
Benefit under CTX alone
Bonner J.A, et al. as presented ASTRO 2008

22. ERBITUX + RT: Overall Survival by Severity of Acne/Rash
1.00
0.75
0.50
0.25
0.00
ERBITUX + RT Grade 2-4 Acne/Rash
Probability of survival (%)
grade 0–1 grade 2-4 n
Median
p=0.002
HR (CI)= 0.49 (0.34 – 0.72)
ERBITUX + RT Grade 0-1 Acne/Rash
Time (Month)
Bonner J.A, et al. as presented ASTRO 2008

23. ERBITUX + RT: Relevant grade 3–5 adverse events
RT (n=212)
ERBITUX + RT (n=208)
p-valuea
Mucositis/stomatitis
52%
56%
0.44
Dysphagia
30%
26%
0.45
Radiation dermatitis
18%
23%
0.27
Xerostomia 3% 5%
0.32
Fatigue/malaise 4%
0.64
Acne-like rash 1%
17%
<0.001
Infusion-related reactionsb 0%
0.01
aFisher’s exact test
bListed for its relationship to ERBITUX
Bonner J, et al. N Engl J Med 2006;354:567–578

24. No Phase III Direct Head to Head Comparison.
Cetuximab + Rth
CRT
No Phase III Direct Head to Head Comparison.
Between-Study Comparison of Phase III Studies  20 & months Survival Advantages.
Discretion of The Treating Physician.

25. Disease Specific Survival
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%
Disease Specific Survival
79%
77%
3-Y OAS
76%
61%
0.02

26. Considerable Number of Non-Protocol Patients in CRT Arm.
Inclusion of Higher Number of T-4 Patients in CRT Arm.

27. CT or Erbitux effect (p-value)
Comparison of overall survival advantage of different combinations (MACH-NC meta-analyses, Bonner study)
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%
Neoadjuvant CT +RT1
0.95 (0.88–1.01)
0.10 2%
Concomitant CT + RT1
0.81 (0.76–0.88)
<0.0001 7% 8%
ERBITUX + RT2
0.73 (0.56–0.95)
0.02
10%
aAssuming survival rates of 50% at 2 years and 32% at 5 years in control groups
Pignon JP, et al. Lancet 2000;355:949–955
Bonner J.A, et al. as presented ASTRO 2008

28. ERBITUX+RT provides a high reduction in the risk of death at 5 years
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
Adjuvant CT+RT1
Neoadjuvant CT+RT1
Concomitant CT+RT1
ERBITUX +RT2 0%
-5%
-2%
-5%
-10%
-15%
-20%
-19%
-25%
-30%
-27%
1) Pignon JP, et al. Lancet 2000;355:949–955
2) Bonner J.A, et al. ASTRO 2008

29. 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.
Also there is some published data about the incorporation of Cetuximab into neoadjuvant chemotherapy protocols as Paclitaxel/Carboplatin and TPF with reported higher response rates as well as pathologic complete remissions.
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

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

31. 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.