Protokolle und Indikationen für die
kombinierte Radiochemotherapie
Wilfried Budach
Düsseldorf
Meta-analysis of 93 randomized trials (Pignon et al. 2009)
Individual data of 17,346 patients
Meta-analysis: Induction TPF vs. Induction PF before RT or RT-CHX
Hitt et al. ESMO 2008
MARCH- Meta-analysis on early death (<=day 90)
Pignon et al. Radiother Oncol Web figures 2009
Meta-analysis by tumor site (Blanchard et al. Radiother Oncol 2011)
Meta-analysis of 93 randomized trials (Pignon et al. 2009)
(no head to head comparisons of different chemotherapy schedules)
death
ARO/-AHMO 04-01 TRIAL
Overall Survival
+ 5FU
+ 5FU
V. Budach, ARO 04-01 Trial, ESTRO 2010
Concomitant Chemoradiation: Which schedule should be used?
• Many consider 100 mg/m² cisplatin (d1, 22, 43) standard
• Fractionated cisplatin e.g. 30-40 mg/m² weekly or 20mg/m²
d1-5 + d29-33 seem to be equally effective and less toxic
• Mitomycin C (10 mg/m² weeks 1+5) + 5-FU (600 mg/m² CI
d1-5 + d29-33) has also been shown to be effective
• Carboplatin 70-75 mg/m² + 5-FU 1000 mg/m² CI d 1-4 +
d29-33 of RT is also an option
• The exact value of aditional 5-FU is unknown
Medikamentöse Tumortherapie der Kopf-, Hals-Tumoren
W. Budach, Düsseldorf
Meta-analysis of 93 randomized trials (Pignon et al. 2009)
Age dependence
death
Meta-Analysis : Which fractionation is the best?
End Point: Locoregional Recurrence
Hyperfractionation
Accelerated fractionation
Very accelerated fractionation
(with moderate dose escalation)
vs. conventional fractionation
without decreased total dose
vs. conventional fractionation
with decreased total dose
vs. conventional fractionation
Bourhis, Lancet 2006
Meta-Analysis : Which fractionation is the best?
Bourhis, Lancet 2006
End Point: Overall Survival
Hyperfractionation
Accelerated fractionation
Very accelerated fractionation
(with moderate dose escalation)
vs. conventional fractionation
without decreased total dose
vs. conventional fractionation
with decreased total dose
vs. conventional fractionation
RTOG 0129: Objective & Study Design
Do we need accelerated RT, if RT is combined with concurrent CHX?
72 Gy + 200 mg/m² Cisplatin
70 Gy + 300 mg/m² Cisplatin
Does 100 mg/m² cisplatin compansate for 1 week longer overall treatment time?
RTOG 0129: Intent to treat analysis
Kian Ang et al. 2010
Toxicity in random. H&N trials: RT vs. RT-CHX (grade
>=III)
“Older random trials” on concurrent Chemoradiation
Toxicity in random. H&N trials: RT vs. RT-CHX (grade
>=III)
“newer random trials” on concurrent Chemoradiation
Multivariate analysis with grade 2–4 RTOG swallowing dysfunction
at 6 months as primary endpoint
n=529
Langendijk et al. Radiother Oncol 2009
Locally advanced head and neck cancer: RT vs. RT + cetuximab
RT (n = 213)
Stadium III und IV
nicht metastasierendes
SCCHN (n = 424)
R
Cetuximab + RT (n = 211)
Initialdosis 400 mg/m²
(1 Woche vor RT)
dann 250 mg/m² + RT
(Wochen 2 – 8)
Stratifiziert durch:
•
•
•
•
KPS
Lymphknotenbeteiligung
Tumor Stadium
RT Regime
•
•
Primärer Endpunkt
Dauer der lokoregionären Kontrolle
Sekundäre Endpunkte
•
Gesamtüberleben (OS)
Progressionsfreies Überleben (PFS)
•
Ansprechrate (RR)
•
Sicherheit
Bonner et al., N Engl J. Med 2006; 354: 567 – 578.
Locally advanced head and neck cancer: RT vs. RT + cetuximab
locoregional control
Bonner et al. NEJM 2006
overall survival
Locally advanced head and neck cancer: RT vs. RT + cetuximab
Overall Survival: Update with 5 years follow up
Bonner et al Lancet Oncol 2010
Locally advanced head and neck cancer: RT vs. RT + cetuximab
Overall survival and cetuximab induced skin rash
BonnerBonner
et al Lancet
Oncol
2010
et al, ASTRO
2008
Locally advanced head and neck cancer: RT vs. RT + cetuximab
Foster plot: Update with 5 years follow up
Bonner et al Lancet Oncol 2010
Radiotherapy vs. radiotherapy + cetuximab: adverse events
Bonner et al. NEJM 2006
RT + Cetuximab: Radiodermatitis
W. Budach et al. NEJM 2007
RT + Cetuximab: Radiodermatitis
EORTC questionnaire
(Giro, Radiotherapy
and Oncology 2009)
Recommended schedules for simultaneous chemo(bio)radiation
Best evidence (2 or more randomized trials)
•Cisplatin 100 mg/m² d 1,22, and 43 of RT
•Cisplatin 30-40 mg/m² weekly
•Cisplatin 12-20mg/m² + 5-FU 600 mg/m² CI d 1-5 and 29-33 of RT
•Mitomycin C 10mg/m² d 5 + 36 + 5-FU 600 mg/m² CI d 1-5 of RT
Good evidence (at least 1 large randomized trial of high quality)
Carboplatin 70-75 mg/m² + 5-FU 1000 mg/m² CI d 1-4 + d29-33 of RT
Cetuximab 400 mg/m² d-8 + weekly Cetuximab 250 mg/m² during RT
Some evidence (at least 1 randomized trial)
Cisplatin 20mg/m² d 1-5 and 29-33 of RT
Cisplatin 6 mg/m² on all RT days
Carboplatin weekly AUC 1.5 during RT
Carboplatin 25 mg/m² on all RT days
Mitomycin 10-15 mg/m² day 1 of RT
5-FU 1000 mg/m² CI d1-4 and d 29-32 of RT
Locally advaned HNC: Treatment Options
Kian Ang et al. ASCO 2011
Kian Ang et al. ASCO 2011
Kian Ang et al. ASCO 2011
Kian Ang et al. ASCO 2011
Kian Ang et al. ASCO 2011
Kian Ang et al. ASCO 2011
Kian Ang et al. ASCO 2011
Postoperative Chemoradiation vs. Radiation
Locoregional tumor control
pT3 R1 or pT4 or ECE or ≥ 3 LN+
pT3 or pT4 or LN+
R1 or ≥ 2 LN+ or ECE
45% ECE
Close margin ?
57% ECE
Close margin: 29%
55% ECE
Close margin 10%
ARO 96-03
Fietkau et. al. ASCO 2006
EORTC
Bernier et. al. NEJM 2004
RTOG
Cooper et. al. NEJM 2004
Meta-analyses: EORTC and RTOG studies
adjuvant RT vs. RT-CHX
J. Bernier et al. 2005
Meta-analyses: EORTC and RTOG studies
adjuvant RT vs. RT-CHX
Subgroup: close margin (<5 mm) or extracapsular extention
Overall survival
J. Bernier et al. 2005
Meta-analyses: EORTC and RTOG studies
adjuvant RT vs. RT-CHX
Subgroup: R0 (≥5 mm) and no extracapsular extention
Overall survival
J. Bernier et al. 2005
Conclusion: adjuvant RT vs. RT-CHX
Concurrent chemoradiation ist standard of care for
high risk patients
(ECE or close margin [<5 mm])
Overall survival in this high risk group is still below
50% at 5 years. DFS at 5 years is 36%
EGFR antagonist have not been show to be effective in
the adjuvant setting
How much surgical safety margin is needed?
Langendijk et al. Cancer 2005
Chemotherapy schedules in combination
postoperative radiotherapy
EORTC
Cisplatin 100 mg/m² days 1,22, and 43 of radiotherapy
RTOG
Cisplatin 100 mg/m² days 1,22, and 43 of radiotherapy
ARO
Cisplatin 20mg/m² days 1-5 and 29-33 of radiotherapy
+ 5-FU 600 mg/m² CI days 1-5 and 29-33 of radiotherapy
Radiotherapy: 5x2 Gy per week to 64 Gy (ARO) - 66 Gy (RTOG /EORTC)
Acute toxicity: adjuvant RT vs. RT-CHX
Grade III/IV mucositis
RT+ Cisplatin
RT
p
EORTC post –OP
41%
21%
0.001
RTOG
30%
18%
0,003
21%
13%
0.038
post –OP
ARO* post –OP
Spätnebenwirkungen Grad III/IV jeweils tendenziell erhöht (nicht signifikant)
*Cisplatin + 5FU
Impact of HPV-status on outcome of different treatment strategies in head & neck cancer
Locoregional control
Overall survival
DAHANCA: RT +/- nimorazole (?)
Overall survival
n=131
CHAIR OP +: RT
Overall survival
RTOG: RT + cisplatin
TAX 324: PF/TPFRT + carboplatin
HPV 16
Promotes tumor induction by:
•
E6 and E7 gene maybe integrated into the human genom
•
E6 decreases p53 function resulting in genetic instability
•
E7 inhibits pRB resulting in loss of cell cycle control
•
upregulation of p16
Impact on radiation response: (Human cervical cancer cell line):
•
Transfection with E6 enhances radiation sensitivity
Shin et al. Int J Radiat Biol. 2010
HPV pos. tumors do not have p53 mutations
Stransky Science 2011
HPV/p16: DAHANCA 6&7 trial CF vs. AF
Locoregional tumor control
Lassen et al. Radiother Oncol 2011
Locally advanced head and neck cancer: RT vs. RT + cetuximab
Foster plot: Update with 5 years follow up
Bonner et al Lancet Oncol 2010
Kian Ang et al. ASCO 2011
Locally advanced unresected head and neck cancer
•
Concurrent Chemoradiation remains the standard of care
•
Concurrent Cetuximab and radiotherapy is an also an option
•
Induction TPF remains investigational
•
Accelerated RT is probably not needed in case of concurrent CHX
•
HPV/p16 positive head and neck cancer are a distinct entity,
however, it is unknown whether different treatments should be
offered for HPV positive and HPV negative disease
•
Future trials should test different treatment strategies for HPV/p16
positive and negative tumors