Dr. Luis M.

Zetina Toaché
Oncomédica. Multimédica
Guatemala
 Manejo Medico
Cáncer de Cabeza y Cuello

Dr. Luis M. Zetina Toache

Oncología Medica
 Epidemiology of SCCHN

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

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

 Cáncer de Cabeza y Cuello

 ACS estima 47560 nuevos casos en 2008

 Cavidad oral, faringe y laringe
 3% del total de nuevos casos de cáncer en
USA
 11260 muertes por Ca de C Y C
 Etiología: alcohol, tabaco e infección por HPV
 Alta incidencia de segundos primarios en
pulmón y esófago
8
 RAZONES DEL INCREMENTO EN INCIDENCIA
FACTORES HEREDITARIOS FACTORES PERSONALES

ANCESTROS

TABACO

EXPOSICION DIETA CONSUMO

AL SOL O
VIRUS DE ALCOHOL
RADIACION
PARASITOS

FACTORES AMBIENTALES ESTILO DE VIDA

 HPV and SCCHN
• HPV-16 > HPV-18

• Oropharynx: Palatine and lingual tonsils

• < tobacco exposure; < alcohol use
• Younger age (median 49 vs 58)
• Favourable survival
• Role of anti-EGFR therapy for HPV-positive
tumors?
Gillison M, et al. J Natl Canc Inst. 2000;92:709–20; Weinberger et al. J Clin Oncol 2006;24: 736–747; Smith et al.
Cancer Epidem Biomarkers Prev 2008;17: 2087–96
 HPV-associated SCCHN is a distinct
genetic entity

HPV+ HPV-
D cyclins D cyclins

p16INK4A p16INK4A

pRb pRb

p53 WT p53 MU

Wilczynski SP, et al. Am J Pathol 1998;152:145–56; Andl T, et al. Cancer Res 1998;58:5–13; Klussman JP, et al.
Am J Pathol 2003;162:747–53; Balz V, et al. Cancer Res 2003;63:1188–91; Wiest T. Oncogene 2002;21:1510–7
 Tumores con Desregulación
HER1/EGFR

Gliomas

Cabeza y Cuello

Mama
Pulmón
Esofago
Renal
Gastrico
Colorectal
Ovario Pancreas

Vejiga Cervix
Prostata

Salomon DS, Brandt R, Ciardiello F, et al. Crit Rev Oncol Hematol. 1995;19:183-232.
Woodburn JR. Pharmacol Ther. 1999;82:241-250.
 Incidencia de Expresión
EGFR EN TUMORES SOLIDOS
TIPO CANCER EXPRESION
EGFR %
NSCLC 40-80

SCCHN 95

COLON 25-75%
RECTO
GLIO 40-60
BLASTOMA
PROSTATA 40-100

ESOFAGO 45-80
 Cambios en el tratamiento
del cancer
 Prevención
 Diagnóstico
 Conocimiento
-Biología Tumoral
 Tratamiento
- Mejores Técnicas Quirúrgicas
- Preservación órganos
- Radioterapia
- Radioquimioterapia
- Hormonoterapia
- Quimioterapia
- Drogas Efectos secundarios
- Nuevas drogas terapeuticas
-Terapias Blanco Biologicas
 ACTIVACION DE LA CELULA TUMORAL POR
DIFERENTES
FACTORES DE CRECIMIENTO

VEGF
EGFR
AVASTIN ERBITUX

GLEEVEC
TARCEVA

INHB ATP

HERCEPTIN CD-20
HER-2 MABTHERA
 “ It is much more important to know
what kind of patient has a disease,
than to know what kind of disease a
patient has”
Caleb Parry. 18th Century physician, Bath.

“We used to think our fate was in our stars.

Now we know, in large measure, our fate is
in our genes”
J.D Watson. Time Magazine 20 March 1989
 CARCINOMA CABEZA Y CUELLO
(HISTORIA)

 Etapas Clínicas I y II. Modalidad Cirugía o RT

 1970. Etapas clínicas localmente avanzadas (III-IV Mo)

el tratamiento Standard. Cirugía RT

 1980. Debido a los resultados pobres de terapia “tradicional” se

inicia ensayos con quimioterapia
- Neoadyuvante (pre cirugia )
- Adyuvante (post cirugia )
- Combinacion con RT (post cirugia)
Concomitante o secuencial

 QT en etapas tempranas para preservación de órgano

 Carcinoma de Cabeza y Cuello
(historia)
 Durante los últimos años se ha demostrado progreso

- Mejor Control local

- Menor incidencia de recurrencias sistémicas
- Mejoria en SV libre de enfermedad
- Mejoría en Sobrevida global
- Mejoría en Calidad de vida
Laringe
Hipofaringe
 Table 1. Annual Change in Death Rates Between 1990-
1997 for Selected Tumor Types and Patients
Sites Mortality Rate (% Change)
All -0.8
Melanoma +0.1
Non-Hodgkin's lymphoma +1.7
Urinary bladder -0.3
Lung -0.5
Colon/rectum -1.8
Female breast -2.1
Prostate -2.2
Oral cavity/pharynx -2.6
   Men -2.8
      White -2.6
      Black -3.8
   Women -2.3
      White -2.3
      Black -2.5
Ries LAG Cancer 2000 ; 88: 2398-2424
Table 8. Stage IV Nasopharyngeal Cancer:
Change in Overall Survival, 1980-2000

Treatment % 5-Year Survival

RT without salvage <30

RT with salvage ±40

Concurrent CT + RT 50-55

Sequential CT     RT
  50-55

RT     CT
  50-55

CT + RT     CT
  75

CT     CT + RT
  >90

CT = chemotherapy

RT = radiotherapy
 MACH-NC analysis: Survival benefit of
adding chemotherapy to local treatment
Absolute survival benefit at 5 years: 8% (CRT)
CRT regimena a
50 concomitant trials Hazard ratio
Post-operative RT 0.80
Conventional RT 0.83
Altered fractionated RT 0.73

Mono-CT 0.84
Poly-CT 0.77
Platinum-based CT 0.75 p<0.01
Other CT 0.86

Pooled 0.81 (p<0.0001)

CT, chemotherapy; CRT, chemoradiation; RT, radiotherapy

Bourhis J, et al. J Clin Oncol 2004;22:5505. Updated data presented at ASCO 2004
 Table 3. Meta-analysis of Concurrent Chemoradiotherapy vs
Radiotherapy in Patients With Advanced Head and Neck Cancers:
Mortality

Stratum and Treatment Risk Difference (%) P Value*

Overall results† 11 <.00001

Conventional RT both arms 9.2 .00041

RT same both arms, not conventional 16.6 .00008

Platinum-based CT‡ 12.1 <.0001

Mitomycin-C based CT
(radiosensibilizador) 14 .032

5-Fluorourcil-based CT 10.2 .11

Bleomycin-based CT 5 .36

Single agents only 10.7 .0004

Combination CT regimens 11.2 .0009

Combination cisplatin-5FU ( R: 65-
70%) 15.3 <.0001
Table 4. Phase III Randomized Trials Comparing Concomitant Chemotherapy-Radiation
Therapy vs Radiation Therapy Alone in Squamous Cell Head and Neck Cancers

Authors Site Treatment Overall Survival (%) Year P Value

Merlano et al[18] All RT 10 5 <.05
    RT, PF 24    
Brizel et al[19] All RT bid 34 3 .07
    RT, PF 55    
Wendt et al[20] All RT bid, PF 24 3 <.05
    RT bid, PF 49    
Calais et al[21] Oropharynx RT bid 31 3 <.05
    RT bid, CF 51    
Jeremic et al[22] All RT bid 25 5 .0075

    RT bid, P daily 46    

Adelstein et al[23] All RT 20 3 .016

    RT, P 37    
    RT, PF ± S 29    
Staar et al[24] Oropharynx/hypopharynx RT bid 39 2 .09
    RT bid, CF 44    
Table 2. Possible Mechanisms of Interaction Between
Chemotherapy and Radiation Therapy

Modification of the slope of the dose-response curve.

Decrease in accumulation or inhibition of repair of

sublethal damage.

Inhibition of repair of potentially lethal damage.

Induction of tumor re-oxygenation.

Selective cytotoxicity and/or radiosensitization of

hypoxic cells.

Increase in apoptosis.
 Complicaciones y limitaciones
de combinacion RT-QT
 Radioterapia con fraccionamiento acelerado
 Radioterapia Hiperfraccionada
 Drogas radiosensibilizadoras
- Mitomicina
- 5 FU
- Gemcitabine
- Platinos
- Taxanos

 LIMITACION ES TOXICIDAD SEVERA

CRT: Significant increase in acute toxicity
Acute adverse effects: Grade ≥3

Mucositis p<0.01

Dermatitis p<0.05

RT alone (n=140)
Leukopenia
CRT (n=130)

Nausea/emesis

Xerostomia ns

0 10 20 30 40 50 60
Patients (%)

Wendt TG, et al. J Clin Oncol 1998;16:1318–1324

Complicaciones de
RT + QT

MUCOSITIS REQUERIMIENTOS
SEVERA NUTRICIONALES

MIELOTOXICIDAD
CRT is associated with more frequent and
longer treatment interruptions than RT

25 10

23%
20 8 8.9

18%

No. of days
Patients (%)

15 6
6.2

10 4

5 2

0 0
Unplanned treatment Mean duration of
interruptions1 treatment break2

RT CRT

1
Huguenin P, et al. J Clin Oncol 2004;22:4665–4673; 2Calais G, et al. J Natl Cancer Inst 1999;91:2081–2086
 Delays in RT delivery can adversely
affect patient outcomes
Impact of reduced overall treatment Survival correlated with number
time (OTT) on tumor-site control of RT treatment days missed
100
100
5.5 weeks OTT (n=65)
Tumor-site control (%)

80 80 ≤5 RT treatment

Survival (%)
60 60 days missed
6.5 weeks OTT (n=109)
40 40 >5 RT treatment
days missed
20 20
9.5 weeks OTT (n=35)
0 0
0 20 40 60 0 12 24 36 48 60 72 84

Months after radiotherapy Time (months)

n=209; p<0.00001 n=41; p=0.003

Erikisen JG, et al. Acta Oncol 2005;44:50–58 Alden ME, et al. Radiology 1996;201:675–680
 CRT: Late toxicity
 Analysis of 230 patients receiving
CRT in 3 studies (RTOG 91-11, 97-03,
99-14)
 Factors associated with development
50 of severe late toxicitya
43%
– Older age (p=0.001), advanced T-stage
40
Patients (%)

(p=0.0036), larynx/hypopharynx
primary (p=0.004), neck dissection
30 27% after RT (p=0.018)

20
13% 12% 10%
10

0
Any severe Feeding tube Pharyngeal Laryngeal Death
late toxicity dependence dysfunction dysfunction
>2 yrs post-RT
Chronic grade 3-4 pharyngeal/laryngeal toxicity and/or requirement for feeding tube >2 years after registration and/or
potential treatment-related death within 3 years

Machtay M, et al. J Clin Oncol 2008;26: 3582-3589

Preclinical evidence: Antitumor activity
of ERBITUX + RT in vivo

Huang SM, Harari PM. Clin Cancer Res 2000;6:2166–2174

 Racional para el uso de
APS Monoclonales contra EGFR

 EGFR se sobre expresa en 90% de casos SCCHN

 Sobre expresión de EGFR, se asocia a mal pronóstico

 Sobre expresión de EGFR, se encuentra en etapas

tempranas de SCCHN y aun en lesiones pre malignas

 Inhibición de EGFR-TK , disminuye el crecimiento de

modelos animales de xeno injertos de SCCHN
 Radiotherapy plus Cetuximab for Squamous-
Cell Carcinoma of the Head and Neck
Volume 354:567-578     February 9, 2006     Number 6

James A. Bonner, M.D., Paul M. Harari, M.D., Jordi Giralt, M.D., Nozar Azarnia, Ph.D., Dong M.
Shin, M.D., Roger B. Cohen, M.D., Christopher U. Jones, M.D., Ranjan Sur, M.D., Ph.D., David
Raben, M.D., Jacek Jassem, M.D., Ph.D., Roger Ove, M.D., Ph.D., Merrill S. Kies, M.D., Jose
Baselga, M.D., Hagop Youssoufian, M.D., Nadia Amellal, M.D., Eric K. Rowinsky, M.D., and K. Kian
Ang, M.D., Ph.D.
 ERBITUX + RT in locally advanced
SCCHN: Phase III study design
RT (n=213)
Stage III and IV
non-metastatic
SCCHN R
ERBITUX + RT (n=211)
(n=424) ERBITUX initial dose (400 mg/m2)
Stratified by 1 week before RT
ERBITUX (250 mg/m2)
• KPS
+ RT (weeks 2–8)
• Nodal involvement
• Tumor stage
• RT regimena
Primary endpoint: Duration of locoregional control
Secondary endpoints: OS, PFS, RR, and safety
a
Investigators’ choice

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

 Radiotherapy Regimens.

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

Bonner, J. A. et al. N Engl J Med 2006;354:567-578
 Kaplan-Meier Estimates of Locoregional Control among All Patients Randomly Assigned to
Radiotherapy plus Cetuximab or Radiotherapy Alone.

•Hazard ratio=0.74 (95% CI: 0.57–0.97)

•Log-rank p=0.03

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

 Kaplan-Meier Estimates of Overall Survival among All Patients Randomly Assigned to
Radiotherapy plus Cetuximab or Radiotherapy Alone.

Hazard ratio=0.74 (95% CI: 0.57–0.97)

Log-rank p=0.03

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

 ERBITUX + RT:
Relevant grade 3–5 adverse events
Adverse event RT ERBITUX + p-valuea
(n=212) RT (n=208)
Mucositis/stomatitis 52% 56% 0.44
Dysphagia 30% 26% 0.45
Radiation dermatitis 18% 23% 0.27
Xerostomia 3% 5% 0.32
Fatigue/malaise 5% 4% 0.64
Acne-like rash 1% 17% <0.001
Infusion-related reactionsb 0% 3% 0.01

• Median duration of any mucositis or dysphagia in the overall

population was 12–13 weeks and similar in both treatment groups
a
Fisher’s exact test Bonner J, et al. N Engl J Med 2006;354:567–578
b
Listed for its relationship to ERBITUX
 Survival advantage with ERBITUX + RT
compared to CRT vs RT
p=0.03
ERBITUX + RT1 20

p=0.15 (not significant)

Cisplatin
+ hyperfractionated RT2 18

p=0.02
Carboplatin + 5-FU
+ conventional RT3 14

Carboplatin + 5-FU p=0.02

+ hyperfractionated RT (CB)4 7

p=0.02
Mitomycin C + 5-FU
7
+ hyperfractionated RT5

0 5 10 15 20
Median survival advantage (months)
CB, concomitant boost

1
Bonner JA, et al. N Engl J Med 2006; 2Huguenin P, et al. J Clin Oncol 2004; 3Calais G, et al. J Natl Cancer Inst
1999; 4Semrau R, et al. Int J Radiat Oncol Biol Phys 2006 ; 5Budach V, et al. J Clin Oncol 2005
 Comparison of the therapeutic
benefit of ERBITUX + RT vs CRT
101

Median survival advantage (months)

Carboplatin + Cisplatin+ ERBITUX

HFX-RT2 + RT
1
5-FU/FA + HFX RT3

0
0 5 10 15 20

Bonner JA, et al. N Engl J Med 2006;354:567–578; 2Huguenin P, et al. J Clin Oncol 2004;22:4665–4673;
1

3
Calais G, et al. J Natl Cancer Inst 1999;91:2081–2086
ERBITUX in locoregionally advanced SCCHN:
Efficacy summary

• ERBITUX + RT demonstrated significant efficacy benefits over

RT alone

– 20-month increase in median survival

– 26% reduction in risk of death

– 10-month increase in median locoregional control

– 32% reduction in locoregional relapse

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

1RA. SEMANA DE ERBITUX, INPREGNACIÓN
3RA. SEMANA DE ERBITUX, 2DA. SEMANA CON RT
1RA. SEMANA DE ERBITUX, INPREGNACIÓN
4TA. SEMANA DE ERBITUX, 3RA. SEMANA CON RT
4TA. SEMANA DE ERBITUX, 3RA. SEMANA CON RT
RESPUESTA AL FINAL DEL TRATAMIENTO
Efectos secundarios
rash acneiforme
 ASCO 2008 ERBITUX data
in locally advanced
SCCHN
Author Disease Regimen Patient ORR
number
R. B. Tishler et al Locally E-TPF + CRT 19 92% CR
[#6001] advanced (12 for evaluation)
SCCHN
E. Argiris et al Locally Neoadjuvant TPE 39 ORR to TPE 86%
[#6002] advanced Radiation + PE CR 2, PR 30
SCCHN XPE CR 100%
CR 8, PR 20
C. J. Langer et al Locally Definitive RT + EP 61 CR 23% PR 25%
[#6006] advanced SD 31%
SCCHN
B. B. Ma et al Locally IMRT + EP 20 CR 83% PR 17%
[#6055] advanced
NPC
E: ERBITUX, P: Cisplatin, T: Docetaxel
 RTOG 0522: Phase III trial
CRT vs CRT + ERBITUX
Arm 1
Accelerated FX and
concomitant boostb +
Randomized patients CDDP: 100 mg/m2, q3w x 2
with stage III or IVa SCC
of oropharynx, R Arm 2
hypopharynx or larynx, Accelerated and
(n=720) concomitant boostb +
Stratified by
CDDP: 100 mg/m2, q3w x 2
• Larynx vs other ERBITUX: 400 mg/m2, week -1
• KPS: 60–80 vs 90–100 250 mg/m2/week, weeks 2–8
• Regional nodes: N0 vs N1, 2a, 2b vs N2c–3
• 3-D vs IMRTb
a
Exclude T1, any N, and T2 N1
b
3-D: AFX-CB (72 Gy/42 F/6 w) IMRT:
70 Gy/35 F/6wk (bid x 5d)
 RTOG H-0234 phase II trial:
Locally advanced resected
R RT + ERBITUX (400  250 mg/m2, qW)
A + DDP (30 mg/m2, qW)
N
N=243
D RT + ERBITUX (400  250 mg/m2, qW)
Surgical + Docetaxel (15 mg/m2, qW)
resection O
16
M Control 10 Gy 10 Gy
Tumor size (mm)

High risk 14 + Doc

I 12
10 Gy
+ erbitux
Z 10
10 Gy
E 8 +
erbitux
6 + Doc
A431
4
0 10 20 30 40 50
Days after radiation
 Systems medicine-based approach
for cancer therapeutics
Molecular pathology

Individual tumor Molecularly

gene/genome defined
profiling disease
(omics) state

Data integration Personalized

centre therapy

Clinical
characteristics Systems-based Specific
therapeutic targeted
Molecular decision therapies
imaging
 Necessity for systems-based
approach to EGFR therapeutics
Growth factors

Receptors

Core
machineries

Transcription
factors

Cellular
responses

Adapted from Citri & Yarden Nature Reviews Molecular Cell Biology
 Recurrent and/or metastatic SCCHN:
Introduction
 Over 50% of newly diagnosed cases are not cured and
will relapse locally or at distant sites
 10% of newly diagnosed cases present with distant
metastases
 Treatment options: - Chemotherapy (CT)
- Re-irradiation
- Salvage surgery
- Best supportive care (BSC)

 Cisplatin-based CT: - Response rate: 30%

- Overall survival: 6–9 months
 The role of chemotherapy in recurrent
and/or metastatic SCCHN: Summary
 Single agent methotrexate is standard of care

 Cisplatin is probably the most active agent

 Combinations give higher response rate, may have

impact on PFS, but not on overall survival

 Replacing 5FU by paclitaxel in PF 

no difference in terms of survival

 Once platinum-resistance occurs the outlook is very

poor
 ERBITUX: Summary of clinical studies in
recurrent and/or metastatic SCCHN
Type of Disease Treatment Reference
study
Phase I Mixed CDDP + ERBITUX Shin 2001

Phase II Second line ERBITUX alone Vermorken 2007

(platinum Platinum + ERBITUX Baselga 2005
refractory) Herbst 2005
Docetaxel + ERBITUX Knoedler 2008

Phase I/II/III First line Platinum-based Burtness 2005

chemotherapy ± Bourhis 2006
ERBITUX Vermorken 2008

Paclitaxel + ERBITUX Hitt 2007

EXTREME
 EXTREME:
Study design
Randomized

Group A
Either cisplatin (100 mg/m2 IV, d1)
Or carboplatin (AUC 5, d1)
+ 5-FU (1000 mg/m2 IV, d1–4):
3-week cycles
+ ERBITUX 400 mg/m2 initial dose
then 250 mg/m2 weekly
Group B
Either cisplatin (100 mg/m2 IV, d1)
Or carboplatin (AUC 5, d1)
+ 5-FU (1000 mg/m2 IV, d1–4):
3-week cycles

6 chemotherapy cycles maximum

ERBITUX No treatment

Progressive disease or unacceptable toxicity

Vermorken JB, et al. New Engl J Med 2008;359:1116–27

 EXTREME:
Baseline characteristics
Platinum/5-FU Platinum/
+ ERBITUX 5-FU
(n=222) (n=220)
Median age, years (range) 56 (37–80) 57 (33–78)
Male/female, % 89/11 92/8
Recurrence/metastasis, %
Locoregional recurrence 53 54
Metastasisa 47 46
KPS, %
<80 12 11
≥80 88 89
Includes distant metastasis and locoregional recurrence
a
Vermorken JB, et al. New Engl J Med 2008;359:1116–27
 1.0 |
| ||
EXTREME: Overall Survival
| CTX only
CTX + ERBITUX
0.9 |
|
||
0.8 HR [95%CI]: 0.80 [0.64–0.99]
||
|
p=0.04
0.7
Survival probability

|
0.6
10.1 months
10.1 months
0.5 |
7.4 months
7.4 months
0.4
|
|
| |
0.3 | |||| | | |
| | ||
|| ||| || | |
| || || |
|| |||
0.2 || |
|| |||| | | |
| |||
| | | | || | | | | |||| ||| |
0.1

0.0
0 3 6 9 12 15 18 21 24
Patients at risk Survival time (months)
CTX only 220 173 127 83 65 47 19 8 1
CTX + 222 184 153 118 82 57 30 15 3
ERBITUX
Vermorken JB, et al. New Engl J Med 2008;359:1116–27
 Radiology at time of radiotherapy (2002)

Diagnosis: T1N0M0 (pT2N0M0)

oropharyngeal cancer (left tonsil)

Therapy: External radiotherapy

66 Gy (33 fr): tumor site, cervical LN
50 Gy (cum. dose): spinal/supracl. LN

Side effects: Mucositis grade 2

Weight loss 10 kg
MRI (May 2005)
PET-scan
 First-line treatment
EXTREME regimen
Randomized

Group A
Either cisplatin (100 mg/m2 IV, d1)
Or carboplatin (AUC 5, d1)
+ 5-FU (1000 mg/m2 IV, d1–4):
3-week cycles
+ ERBITUX 400 mg/m2 initial dose
then 250 mg/m2 weekly
Group B
Either cisplatin (100 mg/m2 IV, d1)
Or carboplatin (AUC 5, d1)
+ 5-FU (1000 mg/m2 IV, d1–4):
3-week cycles

6 chemotherapy cycles maximum

ERBITUX No treatment

Progressive disease or unacceptable toxicity

Patient was randomized to experimental arm (start 05.05)

Combination PF + ERBITUX: Antitumor effect
MRI (June 2005) MRI (September 2005)

Partial Partial
response response
 Progression after EXTREME
(May 2006)
PET-scan: January 2006 PET-scan: May 2006
 Second-line treatment (June 2006)
Feasibility study TPF + ERBITUX
ERBITUX: a400 mg/m² (d 1, Cy 1), b250 mg/m² iv, d 1, 8, 15
5-FU: 750 mg/m² d 1–5
Cisplatin: 75 mg/m² d 1
Docetaxel: 75 mg/m² d 1

The schedule is repeated on day 22

aover 2 hrs; bover 1 hour

Dexamethasone 8 mg bid (3) /Ciproxin 500 mg bid (d 5–15)

TPF + ERBITUX started

14.06.06
Antitumor effect of TPF + ERBITUX
(September 2006)
Antitumor effect of TPF + ERBITUX
03/12/2007 27/08/2008
 Clinical case: timeframe
Initial diagnosis
and treatment
First recurrence
Second recurrence
Progression

No signs/symptoms
of disease

2002 2003 2004 2005 2006 2007 2008

Starts PF + ERBITUX
Starts TPF + ERBITUX