quimioterapia de induccion en tumores de ......quimioterapia de induccion en tumores de cabeza y...

QUIMIOTERAPIA DE INDUCCION EN TUMORES

DE CABEZA Y CUELLO

¿TODAVIA EN DISCUSION?

Ricardo Hitt CENTRO INTEGRAL ONCOLOGIA CIOCC. MADRID

SEOM , SALAMANCA 2013

Ricardo Hitt 1

DISEÑO ENSAYOS CLINICOS

• Ensayos Fases II: en ocasiones demuestran una

evidencia de beneficio en los pacientes tratados

llegando a ser un tratamiento estándar sin estudios

de confirmación. Ejemplos: MOPP enf Hodgkin,

Glevec en Gist, BEP tumores germinales.

• Suelen ser estudios con población seleccionada y

en centros de referencia

Ricardo Hitt 2

DISEÑO ENSAYOS

• ENSAYOS FASES III : cuales son los

objetivos actualmente?

• Incremento supervivencia: la mayoría de las

enfermedades se tratan en 2º, 3º, ó 4º líneas

• Tiempo a la progresión: aplicable en tumores

metastásicos

• Intervalo libre de enfermedad: mas real cuando se

valora la Remisión Completa

• Preservación de órganos: válido solo en

enfermedades resecables y CURABLES con cirugía.

Ricardo Hitt 3


• META ANÁLISIS: que nivel de evidencia se puede

tener en poblaciones heterogéneas ?

• En puntuales MA se mezclan estudios diseñados

para diferentes enfermedades, con pronósticos

diferentes, localizaciones diversas, tratamientos

dispares y conclusiones que difieren de las

observadas en la práctica clínica. Ejemplo: MACH

(Pignon), incluye: tumores resecables, irresecables,

Laringe, Orofaringe, Cavidad Oral, Platinos, Platinos

subóptimos, No Platinos, diferentes técnicas y dosis

de Radioterapia, etc

Ricardo Hitt 4


• En Tumores de Cabeza y Cuello

(TCC) que esta demostrado?: • Ensayos Fases II: beneficios de la inducción en

centros y población seleccionada, Ejemplos: PPF ,

TPF + QTRT, se consiguen mejores resultados en las

diferentes supervivencias. Desventajas : en

ocasiones datos no reproducibles , requiere una

amplia experiencia y un importante manejo de

soporte.

Ricardo Hitt 5


• ENSAYOS FASES III : datos concluyentes • Tumores Resecables : EORTC , VETERANOS: la

quimioterapia de Inducción seguida de Rt permite reemplazar a la cirugía en tumores de laringe e hipofaringe, logrando semejante supervivencia pero con preservación de órganos.

• ECOG Forastiere: QTI , RT, QTRT demuestran igual supervivencia global pero mejor tasa de preservación de laringe con QTRT y QTI. A 10 años mejoría de ILE con QTI

Ricardo Hitt 6


• ENSAYOS FASES III : datos concluyentes

• Esquemas de inducción con Taxanos superior a PF

clásico. Ejemplos :

• PPF vs PF seguido QTRT estándar (Hitt et al JCO 2005)

• TPF vs PF seguido de QTRT no

estándar(Posner and Vermonken NEJM

2007)

Ricardo Hitt 7

British Journal of Cancer 2000; 83: 1594-1598

GETTEC, French

318, HNSCC, oropharynx stage II-IV

Induction C/T

Cisplatin 100mg/m2, D1

5-FU 1000mg/m2, D1-D5 q3w, 3 cycles

Operable: Surgery RT

Inoperable: RT


Inoperable: RT

Ricardo Hitt 8

chemotherapy

No chemotherapy

Overall survival p=0.03

chemotherapy

No chemotherapy

Dz-free survival p=0.11

GETTEC, French

Ricardo Hitt 9

Journal of the National Cancer Institute 1994; 86: 265-272

Journal of the National Cancer Institute 2004; 96: 1714-1717

GSTTC, Italy

237, HNSCC, stage III/IV

Induction C/T Operable: Surgery RT

Inoperable: RT


5-FU 1000mg/m2, D1-D5

q3w, 4 cycles

Oral cavity

Oropharynx

Hypopharynx

Para-nasal

sinus


Inoperable: RT

A

B

A B

Operable 29% 27%

Inoperable 71% 73%

Ricardo Hitt 10

All pts

Operable group

Inoperable group

Overall survival

Overall survival

Overall survival

Inoperable Operable

A 24% 3%

B 42% 31%

p value 0.04 0.01

3-yr distant metastasis rate

Ricardo Hitt 11

100 pts, HNSCC stage III/IV

RT alone

CCRT

RT: 66-72Gy, conventional, 1.8-2Gy/fx

5yr OS RFS Dist. Mets-

free survival

OS with primary

site preserve

Local control

without resection

RT 48% 51% 75% 34% 45%

CCRT 50% 62% 84% 42% 77%

p value 0.55 0.04 0.09 0.004 <0.001

Oral cavity 4%

Oropharynx 44%

Hypopharynx 16%

Larynx 36%

Aldelstein DJ et al

Cancer 2000; 88: 876-883

Cisplatin: 20mg/m2/d

5FU: 1000mg/m2/d

Infusion, D1-D4 D22-D25

Primary site resection +/- neck dissection

Residual dz or recurrence

Survival benefit from better local control

Ricardo Hitt 12

New England Journal of Medicine 1991; 324: 1685-1690

Veterans Affairs Laryngeal Cancer Study Group

332 pts, laryngeal SCC stage III/IV

Surgery

Surgery +/- RT

C/T x 2


5FU 1000mg/m2/d x 5d q3w

RT: 5000cGy/25fx Adjuvant RT

Definitive RT

RT: 6600-7600cGy

C/T x 1

Residual disease Poor

respond

2yr DFS OS Recur at

primary

Recur at

regional

Distant

mets

Laryngectomy-

free survival

Surgery 75% 68% 2% 5% 17%

C/T RT 65% 68% 12% 8% 11% 39%

p value 0.12 0.98 0.001 NS 0.001

T1/T2 9%

T3 65%

T4 26%

Glottis 37%

Supraglottis 63%

Ricardo Hitt 13

Journal of National Cancer Institute 1996; 8: 890-899

EORTC

194 pts, hypopharynx SCC stage II/III/IV

Surgery

Surgery +/- RT

C/T x 2


5FU 1000mg/m2/d x 5d q3w

RT: 5000cGy/25fx Adjuvant RT

Definitive RT

RT: 7000cGy

C/T x 1

Residual disease Poor

respond

5yr DFS OS Recur at

local

Recur at

regional

Distant

mets

Laryngectomy-

free survival

Surgery 32% 35% 17% 23% 36%

C/T RT 25% 30% 12% 19% 25% 35%

p value NS NS NS NS 0.041

T2 20%

T3 75%

T4 5%

Pyriform

sinus 78%

Aryepiglottic

fold 22%

Ricardo Hitt 14

New England Journal of Medicine 2003; 349: 2091-2098

RTOG 91-11

518 pts, laryngeal SCC III/IV

Surgery +/- RT

C/T x 2


5FU 1000mg/m2/d x 5d

q3w

CCRT

RT

CCRT: RT 7000cGy/35fx Cisplatin 100mg/m2, q3w

C/T x 1 Residual disease

Poor respond

5yr DFS OS Intact

larynx

LR

control

Distant

mets

A: RT 27% 56% 70% 56% 22%

B: CCRT 36% 54% 88% 78% 12%

C: C/TRT 38% 55% 75% 61% 15%

p 0.02(C v A)

0.006(B v A) NS

0.005(B v C)

0.001(B v A)

0.004(B v C)

0.001(B v A) 0.03(B v A)

RT alone

Speech/swallow : similar

T2 12%

T3 78%

T4 10%

Supraglottis 69%

Glottis 31%

Ricardo Hitt 15

UNRESECTABLE SCCHN

Paccagnella JNCI (Nov 2004)

OVERALL SURVIVAL

5 years: CF 23%; control : 19% (ns) 10 years: CF 16% vs 9% (ns)

unresectable

5 years: 21% vs. 16%

10 years: 8% vs. 6%

P= 0.04

Ricardo Hitt 16

Journal of Clinical Oncology 2005; 23: 8636-8645

382 pts, HNSCC stage III/IV

CF x 3

PCF x 3

Hitt R et al, Spain Paclitaxel 175mg/m2, D1


5FU 500mg/m2/d, D2-D6


5FU 1000mg/m2/d, D1-D5

Oral cavity 13%

Oropharynx 34%

Hypopharynx 23%

Larynx 30%

q3w

q3w

CCRT

Cisplatin 100mg/m2, q3w

RT 7000cGy/35fx

CR or PR>80%

Poor responder

Salvage surgery Resectable 35%

Unresectable 65%

Ricardo Hitt 17

Induction

CR neutropenia mucositis Median

survival

Time to tx

failure

PCF 33% 37% 53% 43m 36m

CF 14% 36% 16% 37m 26m

p value <0.001 <0.001 0.03 0.03

Hitt R et al, Spain

Journal of Clinical Oncology 2005; 23: 8636-8645

Dose density

Cisplatin 5FU Paclitaxel

PCF 91% 98% 99%

CF 81% 91%

p value <0.001 <0.001

Ricardo Hitt 18

Time to Treatment Failure

PF (n= 193), 112 Events

PFT (n= 190), 93 Events

Log-rank, p=0.024

PF (median)= 17.7 (11.4 - 23.9) PFT (median)= 21.7 (14.9 - 28.4)

Ricardo Hitt 19

20

Final results of a randomized Phase III trial

comparing induction chemotherapy (ICT)

with cisplatin/5-FU (PF) or

docetaxel/cisplatin/5-FU (TPF) followed by

chemoradiotherapy (CRT) versus CRT

alone as first-line treatment of

unresectable locally advanced head and

neck cancer (LAHNC)

SPANISH HEAD AND NECK CANCER

GROUP

Hitt et.al ASCO 2009

BEST OF ASCO . Annals

of Oncology (in press)

Ricardo Hitt 20

Safety: Adverse events

21

Grade 3/4 AEs,

% patients

CRT

(N=118)

PF plus

CRT

(N=156)

TPF plus

CRT

(N=153)

Total ICT

(TPF + PF)

(N=309)

Neutropenia 20 38 34 36

Febrile neutropenia 1 3 19 11

Thrombocytopenia 4 10 10 10

Asthenia 3 9 14 11

Mucositis 32 43 41 42

Radiation Dermatitis 4 2 0 1

Ricardo Hitt 21

22

p=0.016

% patients

CRT (N=119)

Combined ICT + CRT (N=234)

51.7

65

Por protocolo

Secondary endpoint: LCR

Ricardo Hitt 22

ICT + CRT

CRT

CRT; median 13.3months

HR=0.747;95% CI 0.575-0.971 P=0.0294

ICT + CRT; median 18.2 months

ICT + CRT

CRT

(months)

Tiempo libre de evento

Ricardo Hitt 23

POR PROTOCOLO

Fracaso al tratamiento

CRT ICT + CRT


CRT; median 6.1 months

HR=0.646;95% CI 0.501-0.835 P= <0.001

CRT

ICT + CRT

Ricardo Hitt 24

POR PROTOCOLO

Tiempo libre de evento

(months)

CRT

ICT + CRT


Log-Rank p=0.426


CRT

ICT + CRT

Ricardo Hitt 25

INTENCIÓN DE TRATAR

CRT

ICT + CRT

CRT

ICT + CRT


Log-Rank p=0.3259


(months)

Ricardo Hitt 26

Fracaso al tratamiento INTENCIÓN DE TRATAR

Head and Neck Cancer

Pretreatment considerations

Comorbid chronic diseases

• Pulmonary

• Cardiovascular

• Digestive

Malnutrition

• Resulting from poor dietary habits or symptoms

• Severe in over 25% of patients

Oral health

• Periodontal disease, infections, and caries common

• Dental rehabilitation indicated prior to radiotherapy

Schantz SP, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;797-860.

Ricardo Hitt 27

CRT: Significant increase in

acute toxicity

Acute adverse effects: Grade ≥3

p<0.05

ns

p<0.01

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

0 10 20 30 40 50 60

Xerostomia

Nausea/emesis

Leukopenia

Dermatitis

Mucositis

RT alone (n=140)

CRT (n=130)

Ricardo Hitt 28

CRT: Late toxicity

• Analysis of 230 patients receiving CRT in 3 studies (RTOG 91-11, 97-03, 99-14)

• Factors associated with development of severe late toxicitya o Older age (p=0.001), advanced T-stage (p=0.0036), larynx/hypopharynx

primary (p=0.004), neck dissection after RT (p=0.018)

10% 12%

27%

13%

43%

0

10

20

30

40

50

Pat

ien

ts (

%)

Any severe

late toxicity

Feeding tube

dependence

>2 yrs post-RT

Pharyngeal

dysfunction

Laryngeal

dysfunction DeatH

a 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 29 Ricardo Hitt

TREMPLIN study: Organ preservation with

Erbitux + RT after induction TPF

Lefebvre J, et al. J Clin Oncol 2013;31:853–859

71% could receive the full Erbitux protocol

43% could receive the full cisplatin protocol

Previously untreated SCC larynx/hypopharynx

Suitable for total laryngectomy

Erbitux

R ≥PR

Total laryngectomy +

postoperative RT

TPF

(3 cycles, q3w)

(n=153)

RT (70 Gy)

<PR

56 pts

60 pts

116 (76%) pts

q3w: every 3 weeks; R: randomized

Primary endpoint: larynx preservation 3 months post treatment Secondary endpoints: Preservation of larynx function 18 months after end of treatment, OS, tolerance to and compliance with treatment, feasibility of salvage surgery

Cisplatin

RT (70 Gy)

Ricardo Hitt 31

TREMPLIN study: High rate of protocol

modification due to acute toxicity with Chemo + RT


Cisplatin + RT n=58* (%)

Erbitux + RT n=56 (%)

Protocol modification due to acute toxicity

33 (57.0) 19 (33.9)

Grade 3–4 mucositis 27 (46.6) 25 (44.6)

Grade 3–4 in-field skin toxicity 15 (25.9) 32 (57.1)

Grade 3–4 laryngoesophageal toxicity 5 (8.6) 5 (8.9)

Renal toxicity (any grade) 9 (15.5) 0 (0.0)

* 2 patients did not start treatment in the cisplatin arm

Ricardo Hitt 32

TREMPLIN study: Erbitux preserves organ

function in locally advanced SCCHN


*3 months after end of treatment

**18 months after end of treatment

For patients who were randomized (n=116 [76%])

Primary

endpoint*

● Chemo + RT is associated with acute and long-term toxicity

● Erbitux + RT shows a manageable, well-tolerated profile

Erbitux + RT Chemo + RT

Secondary

endpoints** 92

87

95

89

82

93

0 20 40 60 80 100

Overall

survival

Larynx function

preservation

Larynx

preservation

Patients (%)

Ricardo Hitt 33

TREMPLIN study: Overall survival (ITT)


100

80

60

40

20

0

Overa

ll surv

ival in

%

Patients at risk Chemo + RT 60 56 (0.93) 51 (0.84) 32 (0.78) 13 (0.70)

Erbitux + RT 56 52 (0.93) 45 (0.82) 25 (0.71) 11 (0.71)

Months

Up to 18 months HR: 0.98 (95% CI: 0.26, 3.66), log-rank: p=0.68

Up to 36 months HR: 0.84 (95% CI: 0.34, 2.08), log-rank: p=0.50

Erbitux + RT

Chemo + RT

0 12 24 36 48 60

ITT: intent to treat

Ricardo Hitt 34

TREMPLIN study:

Pronounced late toxicity profile for Chemo + RT


Cisplatin n=58* (%)

Erbitux n=56 (%)

Residual renal dysfunction at last evaluation (all grade 1)

13 (22.4) 0 (0.0)

4 cycles 5 cycles 6 cycles

3% 5%

14%

Grade 3/4 mucosal toxicity 2 (3.5) 1 (1.8)

Grade 3/4 osteoradionecrosis 1 (1.7) 1 (1.8)

Grade 3/4 xerostomia 6 (10.3) 5 (8.9)

Grade 3/4 subcutaneous fibrosis 4 (7.0) 1 (2.0)

Grade 3/4 neuropathy 2 (3.4) 0 (0.0)

*2 patients did not start treatment in the cisplatin arm

Ricardo Hitt 35

DISEÑO ENSAYOS

CLINICOS

• META ANÁLISIS : Datos Concluyentes

• Taxane-Cisplatin-Fluorouracil As Induction Chemotherapy in Locally Advanced Head and Neck Cancers: An Individual Patient Data Meta-Analysis of the Meta-Analysis of Chemotherapy in Head and Neck Cancer Group

• Pierre Blanchard, Jean Bourhis, Benjamin Lacas, Marshall R. Posner, Jan B. Vermorken, Juan J. Cruz Hernandez, Abderrahmane Bourredjem, Gilles Calais, Adriano Paccagnella, Ricardo Hitt, and Jean-Pierre Pignon , on behalf of the Meta-Analysis of Chemotherapy in Head and Neck Cancer, Induction Project, Collaborative Group

• JCO Aug 10, 2013:2854-2860; DOI:10.1200/JCO.2012.47.7802.

Ricardo Hitt 35

Survival curves for (A) overall survival, (B) progression-

free survival, (C) locoregional failure, and (D) distant

failure.

Blanchard P et al. JCO 2013;31:2854-2860

Ricardo Hitt 36

ROLE OF PRIMARY

CHEMOTHERAPY Neoplasms in which Chemotherapy is the Primary Therapeutic Modality for Localized Tumors

-Large cell lynphoma

-Lymphoblastic lymphoma

-Wilms’ tumor

-Embryonal rhabdomyosarcoma

-Small cell lung cancer?

-Central nervous system lymphoma

DeVita 2004

Ricardo Hitt 37

ROLE OF PRIMARY

CHEMOTHERAPY

Neoplasms in which Primary Chemotherapy Can Allow Less Mutilating Surgery:

-Anal carcinoma

-Bladder carcinoma

-Breast cancer

-Laryngeal cancer -Osteogenic sarcoma

-Soft tissue sarcoma

Ricardo Hitt 38

ROLE OF PRIMARY

CHEMOTHERAPY

Neoplasms in which Clinical Trials Indicate an Expanding Role for Primary Chemotherapy in the Future

-Non-small cell lung cancer

-Bladder cancer

-Cervical cancer

-Gastric cancer

-Head and Neck Cancer -Pancreas cancer

-Prostate cancer

Ricardo Hitt 39

CONCLUSIONES La quimioterapia de inducción en tumores de cabeza y cuello tras 20 años de desarrollo ha demostrado: PERMITIR PRESERVACIÓN DE ÓRGANOS MEJORÍA DE SUPERVIVENCIA EN TUMORES IRRESECABLES MEJOR CONTROL LOCO-REGIONAL EN TUMORES IRRESECABLES INCREMENTO DE TOXICIDAD CUANDO SE COMBINA CON QTRT SER FACTIBLE SOLO EN POBLACIÓN SELECCIONADA Y CENTROS CON EXPERIENCIA SE PODRÍA PLANTEAR ESQUEMAS MENOS TÓXICOS CON CETUXIMAB EN INDUCCIÓN?

Ricardo Hitt 40

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