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8/9/2019 Cancer Cabeza y Cuello
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Manejo Medico
Cncer de Cabeza y Cuello
Dr. Luis M. Zetina Toache
Oncologa Medica
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Squamous cell carcinoma of thehead and neck (SCCHN): 98 000
new cases in Europe annually
SCCHN: mortality in Europeis 43 000 annually
SCCHN accountsfor 6% of all
malignanciesWorldwide annualincidence of SCCHN:
485 000 new patients; 261000 deaths
Epidemiology of SCCHN
GLOBOCAN 2002 (http://www-dep.iar.fr)
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Cncer de Cabeza y Cuello
ACS estima 47560 nuevos casos en 2008
Cavidad oral, faringe y laringe
3% del total de nuevos casos de cncer en USA11260 muertes por Ca de C Y C
Etiologa: alcohol, tabaco e infeccin por HPV
Alta incidencia de segundos primarios en pulmn
y esfago
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8
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FACTORES HEREDITARIOS FACTORES PERSONALES
FACTORES AMBIENTALES ESTILO DE VIDA
RAZONES DEL INCREMENTO EN INCIDENCIA
CONSUMO
DEALCOHOL
TABACO
DIETA
VIRUSPARASITOS
EXPOSICION
AL SOL O
RADIACION
ANCESTROS
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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;92:70920; Weinberger et al. J Clin Oncol 2006;24: 736747; Smith et al.Cancer Epidem Biomarkers Prev 2008;17: 208796
HPV and SCCHN
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HPV-associated SCCHN is a distinct geneticentity
MUp53WTp53
pRbpRb
p16INK4Ap16INK4A
D cyclinsD cyclins
HPV-HPV+
Wilczynski SP, et al. Am J Pathol 1998;152:14556; Andl T, et al. Cancer Res 1998;58:513; Klussman JP, et al. AmJ Pathol 2003;162:74753; Balz V, et al. Cancer Res 2003;63:118891; Wiest T. Oncogene 2002;21:15107
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Tumores con Desregulacin
HER1/EGFR
Salomon DS, Brandt R, Ciardiello F, et al. Crit Rev Oncol Hematol. 1995;19:183-232.
Woodburn JR. Pharmacol Ther. 1999;82:241-250.
Mama
Esofago
Gastrico
PancreasOvario
CervixProstata
Vejiga
Colorectal
Renal
Pulmn
Gliomas
Cabeza y Cuello
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Incidencia de Expresin
EGFR EN TUMORES SOLIDOS
TIPO CANCER EXPRESIONEGFR %
NSCLC 40-80
SCCHN 95
COLON RECTO 25-75%
GLIOBLASTOMA
40-60
PROSTATA 40-100
ESOFAGO 45-80
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Cambios en el tratamiento
del cancer
Prevencin
Diagnstico
Conocimiento
-Biologa Tumoral Tratamiento
- Mejores Tcnicas Quirrgicas
- Preservacin rganos
- Radioterapia
- Radioquimioterapia
- Hormonoterapia
- Quimioterapia
- Drogas Efectos secundarios
- Nuevas drogas terapeuticas
-Terapias Blanco Biologicas
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ACTIVACION DE LA CELULA TUMORAL POR
DIFERENTES
FACTORES DE CRECIMIENTO
VEGF
HER-2
CD-20
EGFR
INHB ATP
AVASTIN
HERCEPTIN
GLEEVECTARCEVA
ERBITUX
MABTHERA
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It is much more important to know
what kind of patient has a disease,
than to know what kind of disease a
patient hasCaleb 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 genesJ.D Watson. Time Magazine 20 March 1989
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CARCINOMA CABEZA Y CUELLO
(HISTORIA)
Etapas Clnicas I y II. Modalidad Ciruga o RT
1970. Etapas clnicas localmente avanzadas (III-IV Mo)
el tratamiento Standard. Ciruga 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 preservacin de rgano
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Carcinoma de Cabeza y Cuello
(historia)
Durante los ltimos aos se ha demostrado progreso
- Mejor Control local
- Menor incidencia de recurrencias sistmicas- Mejoria en SV libre de enfermedad
- Mejora en Sobrevida global
- Mejora en Calidad de vida
Laringe
Hipofaringe
a e nnua ange n ea a es
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Sites Mortality Rate (% Change)
All -0.8
Melanoma +0.1Non-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 -2.6Black -3.8
Women -2.3
White -2.3
Black -2.5
a e . nnua ange n ea a esBetween 1990-1997 for Selected Tumor Types
and Patients
Ries LAG Cancer 2000 ; 88: 2398-2424
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Table 8. Stage IV Nasopharyngeal Cancer:Change in Overall Survival, 1980-2000
Treatment % 5-Year Survival
RT without salvage 90
CT = chemotherapy
RT = radiotherapy
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MACH-NC analysis: Survival benefit of
adding chemotherapy to local treatment
CRT regimena 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
Other CT 0.86
Pooled 0.81 (p
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Table 3. Meta-analysis of Concurrent Chemoradiotherapy vs Radiotherapyin Patients With Advanced Head and Neck Cancers: Mortality
Stratum and Treatment Risk Difference (%) PValue*
Overall results 11
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Table 4. Phase III Randomized Trials Comparing Concomitant Chemotherapy-RadiationTherapy vs Radiation Therapy Alone in Squamous Cell Head and Neck Cancers
Authors Site Treatment Overall Survival (%) Year PValue
Merlano et al[18] All RT 10 5
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Table 2. Possible Mechanisms of Interaction BetweenChemotherapy and Radiation Therapy
Modification of the slope of the dose-response curve.
Decrease in accumulation or inhibition of repair of sublethaldamage.
Inhibition of repair of potentially lethal damage.
Induction of tumor re-oxygenation.
Selective cytotoxicity and/or radiosensitization of hypoxic cells.
Increase in apoptosis.
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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
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CRT: Significant increase in acute toxicity
Acute adverse effects: Grade 3
p
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Complicaciones de
RT + QT
MUCOSITISSEVERA
REQUERIMIENTOSNUTRICIONALES
MIELOTOX
ICIDAD
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CRT is associated with more frequent andlonger treatment interruptions than RT
RT CRT
1Huguenin P, et al. J Clin Oncol 2004;22:46654673; 2Calais G, et al. J Natl Cancer Inst 1999;91:20812086
0
5
10
15
20
25
23%
18%
0
2
4
6
8
10
6.2
8.9
Unplanned treatmentinterruptions1
Mean duration oftreatment break2
Patients(
%)
No.ofda
ys
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100
80
60
40
20
0 4020 600
Months after radiotherapy
Tumor-sitecontr o
l(%)
9.5 weeks OTT (n=35)
6.5 weeks OTT (n=109)
5.5 weeks OTT (n=65)
n=209; p5 RT treatmentdays missed
100
80
60
40
20
0 60 840 7212 24 36 48
n=41; p=0.003
Alden ME, et al. Radiology 1996;201:675680
Survival correlated with numberof RT treatment days missed
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CRT: Late toxicity
Analysis of 230 patients receivingCRT in 3 studies (RTOG 91-11, 97-03,
99-14)
Factors associated with development
of severe late toxicitya
Older age (p=0.001), advanced T-stage
(p=0.0036), larynx/hypopharynxprimary (p=0.004), neck dissection
after RT (p=0.018)
10%12%
27%
13%
43%
0
10
20
3040
50
Patients
(%
)
Any severelate toxicity
Feeding tubedependence
>2 yrs post-RT
Pharyngealdysfunction
Laryngealdysfunction
Death
a Chronic grade 3-4 pharyngeal/laryngeal toxicity and/or requirement for feeding tube >2 years after registration and/orpotential treatment-related death within 3 years
Machtay M, et al. J Clin Oncol 2008;26: 3582-3589
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Huang SM, Harari PM. Clin Cancer Res 2000;6:21662174
Preclinical evidence: Antitumor activity
of ERBITUX + RT in vivo
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Racional para el uso de
APS Monoclonales contra EGFR
EGFR se sobre expresa en 90% de casos SCCHN
Sobre expresin de EGFR, se asocia a mal pronstico
Sobre expresin de EGFR, se encuentra en etapas
tempranas de SCCHN y aun en lesiones pre malignas
Inhibicin de EGFR-TK , disminuye el crecimiento de
modelos animales de xeno injertos de SCCHN
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Radiotherapy plus Cetuximab for Squamous-Cell
Carcinoma of the Head and Neck
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.
Volume 354:567-578 February 9, 2006 Number 6
http://content.nejm.org/content/vol354/issue6/index.shtmlhttp://content.nejm.org/content/vol354/issue6/index.shtml8/9/2019 Cancer Cabeza y Cuello
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Stage III and IVnon-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 28)
ERBITUX + RT in locally advancedSCCHN: Phase III study design
Bonner J, et al. N Engl J Med 2006;354:567578
aInvestigators choice
R
Primary endpoint: Duration of locoregional control
Secondary endpoints: OS, PFS, RR, and safety
Stratified by
KPS
Nodal involvement
Tumor stage
RT regimena
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Bonner, J. A. et al. N Engl J Med 2006;354:567-578
Radiotherapy Regimens.
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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
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Bonner, J. A. et al. N Engl J Med 2006;354:567-578
Kaplan Meier Estimates of Locoregional Control among All Patients Randomly Assigned toRadiotherapy plus Cetuximab or Radiotherapy Alone.
Hazard ratio=0.74 (95% CI: 0.570.97)Log-rank p=0.03
Kaplan-Meier Estimates of Overall Survival among All Patients Randomly Assigned to Radiotherapy
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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 Radiotherapyplus Cetuximab or Radiotherapy Alone.
Hazard ratio=0.74 (95% CI: 0.570.97)Log-rank p=0.03
ERBITUX RT
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Adverse event 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 5% 4% 0.64
Acne-like rash 1% 17%
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Survival advantage with ERBITUX + RTcompared to CRT vs RT
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
7
7
14
18
20
0 5 10 15 20Median survival advantage (months)
Carboplatin + 5-FU+ conventional RT3
Cisplatin+ hyperfractionated RT2
ERBITUX + RT1
Carboplatin + 5-FU+ hyperfractionated RT (CB)4
Mitomycin C + 5-FU+ hyperfractionated RT5
CB, concomitant boost
p=0.15 (not significant)
p=0.02
p=0.02
p=0.02
p=0.03
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Comparison of the therapeuticbenefit of ERBITUX + RT vs CRT
ERBITUX+ RT1
Cisplatin+HFX-RT2
Carboplatin + 5-FU/FA + HFX RT3
1Bonner JA, et al. N Engl J Med 2006;354:567578; 2Huguenin P, et al. J Clin Oncol 2004;22:46654673;3Calais G, et al. J Natl Cancer Inst 1999;91:20812086
Median survival advantage (months)
0
101
0 5 10 15
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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;354:567578
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1RA. SEMANA DE ERBITUX, INPREGNACIN
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3RA. SEMANA DE ERBITUX, 2DA. SEMANA CON RT
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1RA. SEMANA DE ERBITUX, INPREGNACIN
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4TA. SEMANA DE ERBITUX, 3RA. SEMANA CON RT
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4TA. SEMANA DE ERBITUX, 3RA. SEMANA CON RT
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RESPUESTA AL FINAL DEL TRATAMIENTO
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Efectos secundarios
rash acneiforme
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ASCO 2008 ERBITUX datai l ll d d
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in locally advanced
SCCHN
Author Disease Regimen Patientnumber ORR
R. B. Tishler et al
[#6001]LocallyadvancedSCCHN
E-TPF + CRT 19 92% CR(12 for evaluation)
E. Argiris et al
[#6002]
Locally
advancedSCCHN
Neoadjuvant TPE
Radiation + PE
39 ORR to TPE 86%CR 2, PR 30
XPE CR 100%CR 8, PR 20
C. J. Langer et al
[#6006]LocallyadvancedSCCHN
Definitive RT + EP 61 CR 23% PR 25%SD 31%
B. B. Ma et al
[#6055]LocallyadvancedNPC
IMRT + EP 20 CR 83% PR 17%
E: ERBITUX, P: Cisplatin, T: Docetaxel
RTOG 0522 Ph III t i l
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RTOG 0522: Phase III trialCRT vs CRT + ERBITUX
Stratified by
Larynx vs other
KPS: 6080 vs 90100
Regional nodes: N0 vs N1, 2a, 2b vs N2c3 3-D vs IMRTb
Randomized patients withstage III or IVa SCC of
oropharynx, hypopharynxor larynx,(n=720)
Arm 2
Accelerated and concomitantboostb +CDDP: 100 mg/m2, q3w x 2ERBITUX: 400 mg/m2, week -1250 mg/m2/week, weeks 28
Arm 1Accelerated FX andconcomitant boostb +CDDP: 100 mg/m2, q3w x 2
aExclude T1, any N, and T2 N1b3-D: AFX-CB (72 Gy/42 F/6 w) IMRT:70 Gy/35 F/6wk (bid x 5d)
R
RTOG H-0234 phase II trial:
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RTOG H-0234 phase II trial:
Locally advanced resected
RA
N
D
OM
IZ
E
N=243Surgicalresection
High risk
RT + ERBITUX (400 250 mg/m2, qW)+ DDP (30 mg/m2, qW)
RT + ERBITUX (400 250 mg/m2, qW)
+ Docetaxel (15 mg/m2
, qW)
Days after radiation
Tumor
size(m
m)
0 10 20 30 40 504
6
8
10
12
14
16Control
A431
10 Gy 10 Gy+ Doc10 Gy
+ erbitux
10 Gy+erbitux+ Doc
S t di i b d h
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Molecularlydefineddisease
state
Individual tumorgene/genome
profiling(omics)
Systems-basedtherapeutic
decision
Specifictargetedtherapies
Personalizedtherapy
Data integrationcentre
Clinicalcharacteristics
Molecularimaging
Molecular pathology
Systems medicine-based approach
for cancer therapeutics
Necessity for systems-basedh t EGFR th ti
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Adapted from Citri & Yarden Nature Reviews Molecular Cell Biology
Growth factors
Receptors
Coremachineries
Transcriptionfactors
Cellularresponses
approach to EGFR therapeutics
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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: 69 months
Th l f h th i t
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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 PFno difference in terms of survival
Once platinum-resistance occurs the outlook is verypoor
ERBITUX: Summary of clinical studies in
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ERBITUX: Summary of clinical studies in
recurrent and/or metastatic SCCHN
Type of study Disease Treatment Reference
Phase I Mixed CDDP + ERBITUX Shin 2001
Phase II Second line(platinumrefractory)
ERBITUX alonePlatinum + ERBITUX
Docetaxel + ERBITUX
Vermorken 2007Baselga 2005Herbst 2005
Knoedler 2008
Phase I/II/III First line Platinum-basedchemotherapy
ERBITUX
Paclitaxel + ERBITUX
Burtness 2005Bourhis 2006
Vermorken 2008
Hitt 2007
EXTREME
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EXTREME
EXTREME:
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EXTREME:Study design
Group AEither cisplatin (100 mg/m2 IV, d1)
Or carboplatin (AUC 5, d1)
+ 5-FU (1000 mg/m2
IV, d14):3-week cycles+ ERBITUX 400 mg/m2 initial dose
then 250 mg/m2 weekly
Group BEither cisplatin (100 mg/m2 IV, d1)
Or carboplatin (AUC 5, d1)+ 5-FU (1000 mg/m2 IV, d14):3-week cycles
NotreatmentERBITUX
Randomized
Progressive disease or unacceptable toxicity
6 chemotherapy cycles maximum
Vermorken JB, et al. New Engl J Med 2008;359:111627
EXTREME:
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Baseline characteristics
Platinum/5-FU+ ERBITUX
(n=222)
Platinum/5-FU
(n=220)
Median age, years (range) 56 (3780) 57 (3378)
Male/female, % 89/11 92/8Recurrence/metastasis, %
Locoregional recurrenceMetastasisa
5347
5446
KPS, %
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10.1 months
7.4 months
Patients at risk Survival time (months)CTX onlyCTX +ERBITUX
220 173 127 83 65 47 19 8 1222 184 153 118 82 57 30 15 3
HR [95%CI]: 0.80 [0.640.99]p=0.04
EXTREME: Overall SurvivalCTX onlyCTX + ERBITUX
Surviv
al
probability
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15 18 21 24
|| |
||
| |
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| |
| |
|
|
|
||
||| | | |||| ||| ||||| | | || | | || | ||| | | | | ||| | | |
|| | |
10.1 months
7.4 months
Vermorken JB, et al. New Engl J Med 2008;359:111627
Radiology at time of radiotherapy (2002)
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Radiology at time of radiotherapy (2002)
Diagnosis: T1N0M0 (pT2N0M0)oropharyngeal cancer (left tonsil)
Therapy: External radiotherapy66 Gy (33 fr): tumor site, cervical LN50 Gy (cum. dose): spinal/supracl. LN
Side effects: Mucositis grade 2 Weight loss 10 kg
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MRI (May 2005)
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PET-scan
First-line treatment
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EXTREME regimen
Group AEither cisplatin (100 mg/m2 IV, d1)
Or carboplatin (AUC 5, d1)
+ 5-FU (1000 mg/m2
IV, d14):3-week cycles+ ERBITUX 400 mg/m2 initial dose
then 250 mg/m2 weekly
Group BEither cisplatin (100 mg/m2 IV, d1)
Or carboplatin (AUC 5, d1)+ 5-FU (1000 mg/m2 IV, d14):3-week cycles
NotreatmentERBITUX
Randomized
Progressive disease or unacceptable toxicity
6 chemotherapy cycles maximum
Patient was randomized to experimental arm (start 05.05)
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Combination PF + ERBITUX: Antitumor effect
Partial response
MRI (June 2005)
Partial response
MRI (September 2005)
Progression after EXTREME
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Progression after EXTREME
(May 2006)
PET-scan: January 2006 PET-scan: May 2006
Second-line treatment (June 2006)
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Second-line treatment (June 2006)
Feasibility study TPF + ERBITUX
ERBITUX: a400 mg/m (d 1, Cy 1), b250 mg/m iv, d 1, 8, 15
5-FU: 750 mg/m d 15
Cisplatin: 75 mg/m d 1
Docetaxel: 75 mg/m d 1
The schedule is repeated on day 22aover 2 hrs; bover 1 hour
Dexamethasone 8 mg bid (3) /Ciproxin 500 mg bid (d 515)
TPF + ERBITUX started14.06.06
Antitumor effect of TPF + ERBITUX
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81/83
(September 2006)
Antitumor effect of TPF + ERBITUX
8/9/2019 Cancer Cabeza y Cuello
82/83
03/12/2007 27/08/2008
8/9/2019 Cancer Cabeza y Cuello
83/83
Clinical case: timeframe
2003 20042002 2005 2006
Initial diagnosisand treatment
First recurrence
Second recurrence
Progression
2007 2008
No signs/symptoms ofdisease
Starts PF + ERBITUX
Starts TPF + ERBITUX