Cancer Cabeza y Cuello

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)



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.shtml


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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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Kaplan-Meier Estimates of Locoregional Control among All Patients Randomly Assigned to


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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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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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(September 2006)

Antitumor effect of TPF + ERBITUX


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03/12/2007 27/08/2008


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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

Cancer Cabeza y Cuello

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