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
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
Ricardo Hitt 4
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.
Ricardo Hitt 5
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
Ricardo Hitt 6
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)
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
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
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: 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
Surgery +/- RT
C/T x 2
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/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%
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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
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
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
Tiempo libre de evento
(months)
CRT
ICT + CRT
CRT; median 13.8 months
Log-Rank p=0.426
ICT + CRT; median 14.3 months
CRT
ICT + CRT
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INTENCIÓN DE TRATAR
CRT
ICT + CRT
CRT
ICT + CRT
CRT; median 7.1 months
Log-Rank p=0.3259
ICT + CRT; median 8.9 months
(months)
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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.
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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 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)
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TREMPLIN study: High rate of protocol
modification due to acute toxicity with Chemo + RT
Lefebvre J, et al. J Clin Oncol 2013;31:853–859
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
Lefebvre J, et al. J Clin Oncol 2013;31:853–859
*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)
Lefebvre J, et al. J Clin Oncol 2013;31:853–859
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
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TREMPLIN study:
Pronounced late toxicity profile for Chemo + RT
Lefebvre J, et al. J Clin Oncol 2013;31:853–859
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
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?
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