QUIMIOTERAPIA DE INDUCCION EN TUMORES DE CABEZA Y

QUIMIOTERAPIA DE
INDUCCION EN TUMORES
DE CABEZA Y CUELLO
¿TODAVIA EN DISCUSION?
SEOM , SALAMANCA 2013
Ricardo Hitt
CENTRO INTEGRAL ONCOLOGIA
CIOCC. MADRID
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
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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
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
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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.
Ricardo Hitt
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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
Ricardo Hitt
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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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GETTEC, French
318, HNSCC,
oropharynx
stage II-IV
Ricardo Hitt
Cisplatin 100mg/m2, D1
5-FU 1000mg/m2, D1-D5
Induction C/T
q3w,
3 cycles
Operable: Surgery  RT
Inoperable: RT
Operable: Surgery  RT
Inoperable: RT
British Journal of Cancer 2000; 83: 1594-1598
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chemotherapy
GETTEC, French
Overall
survival
p=0.03
No chemotherapy
chemotherapy
Dz-free
survival
p=0.11
No chemotherapy
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GSTTC, Italy
Cisplatin 100mg/m2, D1
5-FU 1000mg/m2, D1-D5
q3w,
4 cycles
A
Operable: Surgery  RT
Inoperable: RT
237, HNSCC,
stage III/IV
B
Induction C/T
Operable: Surgery  RT
Inoperable: RT
Oral cavity
Oropharynx
A
B
Hypopharynx
Operable
29%
27%
Para-nasal
sinus
Inoperable
71%
73%
Journal of the National Cancer Institute 1994; 86: 265-272
Journal of the National Cancer Institute 2004; 96: 1714-1717
Ricardo Hitt
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All pts
3-yr distant metastasis rate
Overall
survival
Operable
group
Ricardo Hitt
Overall
survival
Inoperable
Operable
A
24%
3%
B
42%
31%
p value
0.04
0.01
Inoperable
group
Overall
survival
11
Aldelstein DJ et al
RT alone
100 pts, HNSCC
stage III/IV
RT: 66-72Gy, conventional, 1.8-2Gy/fx
Cisplatin: 20mg/m2/d
5FU: 1000mg/m2/d
CCRT
Oral cavity
4%
Oropharynx
44%
Hypopharynx
16%
Larynx
36%
Infusion,
D1-D4
D22-D25
Residual dz
or recurrence
Primary site resection +/- neck dissection
5yr
OS
RFS
Dist. Metsfree 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
Survival benefit from better local control
Ricardo Hitt
Cancer 2000; 88: 876-883
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Veterans Affairs Laryngeal Cancer Study Group
Adjuvant RT RT: 5000cGy/25fx
Surgery
332 pts,
laryngeal SCC
stage III/IV
RT: 6600-7600cGy
C/T x 2
T1/T2
9%
T3
65%
T4
26%
Glottis
Supraglottis
C/T x 1
Poor
respond
Cisplatin 100mg/m2, D1
q3w
5FU 1000mg/m2/d x 5d
37%
63%
Definitive RT
Residual
disease
Surgery +/- RT
2yr
DFS
OS
Recur at
primary
Recur at
regional
Distant
mets
Surgery
75%
68%
2%
5%
17%
C/T RT
65%
68%
12%
8%
11%
p value
0.12
0.98
0.001
NS
0.001
Laryngectomyfree survival
39%
New England Journal of Medicine 1991; 324: 1685-1690
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EORTC
Surgery
194 pts,
hypopharynx SCC
stage II/III/IV
RT: 7000cGy
C/T x 2
T2
20%
T3
75%
T4
5%
RT: 5000cGy/25fx
Adjuvant RT
C/T x 1
Cisplatin 100mg/m2, D1
q3w
5FU 1000mg/m2/d x 5d
Poor
respond
Definitive RT
Residual
disease
Surgery +/- RT
Pyriform
sinus
78%
5yr
DFS
OS
Recur at
local
Recur at
regional
Distant
mets
Aryepiglottic
fold
22%
Surgery
32%
35%
17%
23%
36%
C/T RT
25%
30%
12%
19%
25%
p value
NS
NS
NS
NS
0.041
Laryngectomyfree survival
35%
Journal of National Cancer Institute 1996; 8: 890-899
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RTOG 91-11
RT alone
518 pts,
laryngeal SCC
III/IV
CCRT:
RT 7000cGy/35fx
Cisplatin 100mg/m2, q3w
CCRT
C/T x 2
T2
12%
T3
78%
T4
10%
Supraglottis
Glottis
C/T x 1
Cisplatin 100mg/m2, D1
5FU 1000mg/m2/d x 5d
q3w
Poor
respond
69%
31%
Speech/swallow :
similar
Surgery +/- RT
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%
0.005(B v C)
0.004(B v C)
5yr
0.02(C v A)
Ricardo Hitt
Residual
disease
RT
p
NS 0.001(B v A) 0.001(B v A)
0.006(B v A)
New England Journal of Medicine 2003; 349: 2091-2098
0.03(B v A)
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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)
5 years: 21% vs. 16%
unresectable
P= 0.04
10 years: 8% vs. 6%
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Hitt R et al, Spain
Paclitaxel 175mg/m2, D1
Cisplatin 100mg/m2, D2 q3w
5FU 500mg/m2/d, D2-D6
Cisplatin 100mg/m2, q3w
RT 7000cGy/35fx
PCF x 3
382 pts, HNSCC
stage III/IV
CR or PR>80%
CCRT
CF x 3
Oral cavity
13%
Oropharynx
34%
Hypopharynx
23%
Larynx
30%
Poor
responder
Cisplatin 100mg/m2, D1
q3w
5FU 1000mg/m2/d, D1-D5
Salvage surgery
Resectable
35%
Unresectable
65%
Journal of Clinical Oncology 2005; 23: 8636-8645
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Hitt R et al, Spain
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
Dose density
Ricardo Hitt
Cisplatin
5FU
Paclitaxel
PCF
91%
98%
99%
CF
81%
91%
p value
<0.001
<0.001
Journal of Clinical Oncology 2005; 23: 8636-8645
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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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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
2020
Safety: Adverse events
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
Grade 3/4 AEs,
% patients
Ricardo Hitt
2121
Por protocolo
Secondary endpoint: LCR
p=0.016
65
51.7
%
patients
CRT
(N=119)
Ricardo Hitt
Combined
ICT + CRT
(N=234)
2222
POR PROTOCOLO
Tiempo libre de evento
ICT + CRT; median 18.2 months
CRT; median 13.3months
HR=0.747;95% CI 0.575-0.971
P=0.0294
ICT + CRT
CRT
ICT + CRT
(months)
CRT
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POR PROTOCOLO
Fracaso al tratamiento
ICT + CRT; median 14.4 months
CRT; median 6.1 months
HR=0.646;95% CI 0.501-0.835
P= <0.001
ICT + CRT
CRT
ICT + CRT
CRT
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INTENCIÓN DE TRATAR
Tiempo libre de evento
ICT + CRT; median 14.3 months
CRT; median 13.8 months
Log-Rank p=0.426
ICT + CRT
CRT
(months)
ICT + CRT
CRT
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INTENCIÓN DE TRATAR
Fracaso al tratamiento
ICT + CRT; median 8.9 months
CRT; median 7.1 months
Log-Rank p=0.3259
ICT + CRT
CRT
(months)
ICT + CRT
CRT
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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
Mucositis
p<0.01
Dermatitis
p<0.05
RT alone (n=140)
Leukopenia
CRT (n=130)
Nausea/emesis
Xerostomia
ns
0
10
20
30
40
50
60
Acute adverse effects: Grade ≥3
Ricardo Hitt
Wendt TG, et al. J Clin Oncol 1998;16:1318–1324
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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)
50
Patients (%)
•
43%
40
27%
30
20
13%
12%
10%
Laryngeal
dysfunction
DeatH
10
0
Any severe
late toxicity
a Chronic
Feeding tube
dependence
>2 yrs post-RT
Pharyngeal
dysfunction
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
Ricardo
Hitt
Machtay M, et al. J Clin Oncol 2008;26: 3582-3589 29
TREMPLIN study: Organ preservation with
Erbitux + RT after induction TPF
Previously untreated SCC larynx/hypopharynx
Suitable for total laryngectomy
60 pts
Cisplatin
RT (70 Gy)
TPF
(3 cycles, q3w)
(n=153)
≥PR
R
<PR
116 (76%) pts
Total laryngectomy +
postoperative RT
71% could receive the full Erbitux protocol
43% could receive the full cisplatin protocol
q3w: every 3 weeks; R: randomized
Ricardo Hitt
Erbitux
56 pts
RT (70 Gy)
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
Lefebvre J, et al. J Clin Oncol 2013;31:853–859
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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)
5 (8.6)
5 (8.9)
9 (15.5)
0 (0.0)
Grade 3–4 laryngoesophageal toxicity
Renal toxicity (any grade)
* 2 patients did not start treatment in the cisplatin arm
Ricardo Hitt
Lefebvre J, et al. J Clin Oncol 2013;31:853–859
32
TREMPLIN study: Erbitux preserves organ
function in locally advanced SCCHN
Larynx
preservation
93
95
Larynx function
preservation
Primary
endpoint*
82
87
89
92
Overall
survival
0
20
40
60
80
Secondary
endpoints**
100
Patients (%)
Erbitux + RT
Chemo + RT
● Chemo + RT is associated with acute and long-term toxicity
● Erbitux + RT shows a manageable, well-tolerated profile
*3 months after end of treatment
**18 months after end of treatment
For patients who were randomized (n=116 [76%])
Ricardo Hitt
Lefebvre J, et al. J Clin Oncol 2013;31:853–859
33
TREMPLIN study: Overall survival (ITT)
Overall survival in %
100
Erbitux + RT
Chemo + RT
80
60
40
20
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
0
0
12
24
36
48
60
Months
Patients at risk
Chemo + RT
Erbitux + RT
ITT: intent to treat
Ricardo Hitt
60
56
56 (0.93)
52 (0.93)
51 (0.84)
45 (0.82)
32 (0.78)
25 (0.71)
13 (0.70)
11 (0.71)
Lefebvre J, et al. J Clin Oncol 2013;31:853–859
34
TREMPLIN study:
Pronounced late toxicity profile for Chemo + RT
Residual renal dysfunction at last
evaluation (all grade 1)
4 cycles
5 cycles
6 cycles
*2
Cisplatin
n=58* (%)
Erbitux
n=56 (%)
13 (22.4)
0 (0.0)
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)
patients did not start treatment in the cisplatin arm
Ricardo Hitt
Lefebvre J, et al. J Clin Oncol 2013;31:853–859
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 MetaAnalysis 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) progressionfree 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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