QUIMIOTERAPIA DE INDUCCION EN TUMORES DE CABEZA Y CUELLO

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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

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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

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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

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DISEÑO ENSAYOS CLINICOS

• 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

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DISEÑO ENSAYOS CLINICOS

• 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.

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DISEÑO ENSAYOS CLINICOS

• 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

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DISEÑO ENSAYOS CLINICOS

• 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)

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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

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chemotherapy

No chemotherapy

Overall survival p=0.03

chemotherapy

No chemotherapy

Dz-free survival p=0.11

GETTEC, French

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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

Cisplatin 100mg/m2, D1 5-FU 1000mg/m2, D1-D5

q3w, 4 cycles

Oral cavity Oropharynx Hypopharynx Para-nasal

sinus

Operable: Surgery  RT Inoperable: RT

A

B

A B

Operable 29% 27%

Inoperable 71% 73%

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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

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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

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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

Cisplatin 100mg/m2, D1

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%

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

EORTC

194 pts,

hypopharynx SCC stage II/III/IV

Surgery

Cisplatin 100mg/m2, D1

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%

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

RTOG 91-11

518 pts,

laryngeal SCC III/IV

Cisplatin 100mg/m2, D1 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/TRT 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%

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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

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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 Cisplatin 100mg/m2, D2 5FU 500mg/m2/d, D2-D6

Cisplatin 100mg/m2, D1 5FU 1000mg/m2/d, D1-D5

Oral cavity 13%

Oropharynx 34%

Hypopharynx 23%

Larynx 30%

q3w

CCRT

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

CR or PR>80%

Poor

responder

Salvage surgery

Resectable 35%

Unresectable 65%

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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

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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)

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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)

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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

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22

p=0.016

% patients

CRT (N=119)

Combined ICT + CRT

(N=234)

51.7

65

Por protocolo

Secondary endpoint: LCR

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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

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POR PROTOCOLO

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Fracaso al tratamiento

CRT ICT + CRT

ICT + CRT; median 14.4 months CRT; median 6.1 months

HR=0.646;95% CI 0.501-0.835

P= <0.001

CRT

ICT + CRT

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POR PROTOCOLO

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Tiempo libre de evento

(months) CRT

ICT + CRT

CRT; median 13.8 months

Log-Rank p=0.426

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INTENCIÓN DE TRATAR

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CRT; median 7.1 months Log-Rank p=0.3259

(months)

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Fracaso al tratamiento

INTENCIÓN DE TRATAR

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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.

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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)

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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 toxicity^a

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)

12% 10%

27%

13%

43%

0 10 20 30 40 50

Patients (%)

Any severe late toxicity

Feeding tube dependence

>2 yrs post-RT

Pharyngeal dysfunction

Laryngeal

dysfunction Deat^H

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

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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)

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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

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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 (%)

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TREMPLIN study: Overall survival (ITT)

100

80

60

40

20

0

Overall survival 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

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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

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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.

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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

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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

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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

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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

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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?

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