Kurative und potentiell kurative Therapie von HNO

Kurative und potentiell kurative Therapie
von HNO-Tumoren aus der Sicht des
medizinischen Onkologen.
Gabriela KORNEK
Adjuvante Therapie nach radikaler
Resektion
Adjuvante Radiochemotherapie
Warum ?
Radikale Resektion plus Radiotherapie (60 Gy)…
…70-75% nach 2 Jahren rezidivfrei, aber
5-Jahresüberleben < 30%
15-20% entwickeln Fernmetastasen
Analyse der RTOG von >2500 Patienten:
 enge Korrelation zwischen lokaler Tumorkontrolle und
Inzidenz von Fernmetastasen und (38% versus 21%)
 aggressivere Lokaltherapie besser?
Adjuvant CRT: Phase III-Studien
R1, Kapselruptur, perineurale Invasion, > 2 positive LKN
„RTOG“ Cooper JS et al, NEJM 2004
„EORTC“ Bernier J et al, NEJM 2004
459 Pat. randomisiert
RT: 231
RCT: 228
N 2 oder 3 in 94%
334 Pat. randomisiert
RT: 167
RCT: 167
N 2 oder 3 in 57%
Hochrisikokonstellation
Hochrisikokonstellation
 Positive Ränder 17% (vs 19%)
 > 2 LKN or ECS 81% (vs 83%)
 Positive Ränder 31% (vs 26%)
 Positive LKN
 0-1 :43% (vs 44%)
 > 2: 53% (vs 56%)
 Unknown 4% (vs 1%)
 ECS 61% (vs 53%)
 Perineurale Invasion 13% (vs 14%)
Therapieprotokoll
konventionell fraktionierte Radiotherapie (Gesamtdosis: 60-66 Gy)
Cisplatin 100mg/m2, Tag 1, 22, 43
Adjuvant CRT: Phase III-Studien
R1, Kapselruptur, perineurale Invasion, > 2 positive LKN
„RTOG“ Cooper JS et al, NEJM 2004
DFS: HR 0.74; OS: HR 0.84
„EORTC“ Bernier J et al, NEJM 2004
PFS: HR 0.75; OS: HR 0.70
Adjuvant CRT: Phase III-Studien
R1, Kapselruptur, perineurale Invasion, > 2 positive LKN
72
71
124
Bernier J, NEJM 2004
Cooper JS, NEJM 2004
Fietkau R, ASCO 2006
Adjuvante Therapie aus der Sicht des
medizinischen Onkologen
Adjuvante Radiochemotherapie ist Standard (Level 1a)
Gesicherter Benefit:

Kapselruptur

Positive Resektionsränder
Möglicher Benefit:

Stadium III und IV

perineurale Invasion

Vaskuläre Tumoremboli

und/oder klinisch vergrößerte LKN im Level IV-V
Therapieprotokoll
konventionell fraktionierte Radiotherapie (Gesamtdosis: 60-66 Gy)
Cisplatin 100mg/m2, Tag 1, 22, 43
Bernier J, Cooper JS et al, Head Neck 2005
Therapieoptionen bei potentiell
resektablen Larynx-und
Hypopahrynxkarzinom: Organerhalt
Induction CT plus definitive RT vs laryngectomy
plus postoperative RT: VALSG study
•
•
Multi-centered, prospective study
332 pts enrolled with stage 3 or 4 laryngeal cancer
Induction cisplatin
and 5-FU
(2 cycles)
Complete
or
partial
response
PR and CR
assessed
Cisplatin and 5-FU
(1 cycle)
followed by
definitive RT
No tumor
response to CT
R
Surgery and RT therapy
The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 1991;324:1685–1690
Effective larynx preservation with induction CT and
RT without effecting overall survival
Overall population
Surgery arm
Patients requiring
total laryngectomy
CT arm
36%
Laryngeal preservation rate
64%
Estimated 2-year survival
68%
(p=0.9846)
Tumor response to CT
(after 2 cycles)
85%
0
20
40
60
80
100
Percentage of patients
•
•
2-year and 10-year follow up show significant difference in survival
More local recurrences (p=0.0005) but fewer distant metastases
(p=0.0016) in experimental arm
The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 1991;324:1685–1690
Concomitant CT and RT in advanced
laryngeal cancer: RTOG 91–11
•
547 pts enrolled with stage 3 or 4 laryngeal cancer
Induction cisplatin and 5-FU
(2 cycles)
R
PR and CR
assessed
Complete
or
partial
response
Concurrent cisplatin + RT
No tumor
response
Cisplatin and 5-FU
(1 cycle)
followed by
definitive RT
Laryngectomy
followed by RT
RT alone
Forastiere AA, et al. N Engl J Med 2003;349:2091–2098
Improved locoregional control:
RT plus concurrent cisplatin
•
2-year and 5-year overall survival did not differ significantly between
treatment arms
Both CT arms suppressed distant metastasis and resulted in
better DFS
100
Laryngeal preservation
(% of patients)
•
75
RT with concurrent cisplatin
50
Chemotherapy followed by RT
RT alone
25
0
0.0
0.5 1.0
2.0
3.0
4.0
5.0
Years after randomization
Forastiere AA, et al. N Engl J Med 2003;349:2091–2098
Concomitant CT and RT in advanced laryngeal
cancer: 5-year-update of RTOG 91–11
Forastiere AA, et al. N Engl J Med 2003;349:2091–2098
Locally advanced tumor of the head and neck:
randomized phase III trials - DPF versus PF
Author
Tumor
n
CR/PR %
DPF
CR/PR%
PF
p-value
(pro DPF)
survival
(pro DPF)
Taxane
Hitt
(JCO 2005)
III-IV
382
80
68
.001
n.s.
36.8 vs.
42.9 mos
Paclitaxel
Vermorken
(Tax 323)
Nonresectable
358
68
54
.007
0.007
18.8 vs.
14.5 mos
Docetaxel
Posner
(Tax 324)
III-IV
501
72
64
.007
0.006
71 vs. 31
mos
Docetaxel
205
82
60
.0013
n.e.
Docetaxel
Forastiere,
Larynx
GORTEC
resectable
(ASCO 2006)
DPF: Docetaxel + Platin + 5-Fluorouracil, PF: Platin + 5-Fluorouracil
n.s. not significant, n.e. not evaluable, mos months,
TAX 323/EORTC 24971
Vermorken JB; NEJM 357: 1695, 2007
TAX 324
Posner MR; NEJM 357: 1705, 2007
Therapieoptionen bei lokalfortgeschrittenen, nicht-resektablen
HNO-Tumoren
Induction PF  CRT vs DPF  CRT vs CRT
Phase III Trial
Unresectable locally-advanced HNC
CRT
(Cisplatin 100 mg/m2
d1,22, 43)
PF
3 cycles q3w
N=439
CRT
(Cisplatin 100 mg/m2
d1,22, 43)
Surgery
Cisplatin 100 mg/m2 d1, 5-FU 1000 mg/m2/d d1-5 (CIV)
TPF
3 cycles q3w
Neck
dissection
CRT
(Cisplatin 100 mg/m2
d1,22, 43)
Docetaxel 75 mg/m2 d1, Cisplatin 75 mg/m2 d1, 5-FU 750 mg/m2/d d1-5 (CIV) + primary G-CSF after protocol am
endment

Primary endpoint: TTF (Time from randomization to progression, recurrence,
surgery, death, withdrawal due to adverse events or no locoregional control)
 Secondary endpoints: locoregional control, TTP, OS, safety
Hitt et al. ASCO 2009. Abstract 6009
Induction PF  CRT vs DPF  CRT vs CRT
Phase III Trial
Unresectable locally-advanced HNC
CRT
(N=128)
PF plus CRT
(N=156)
DPF plus CRT
(N=155)
56 (25-80)
57 (35-85)
58 (36-78)
Male/female, %
90/10
93/7
94/6
ECOG PS 0/1, %
26/74
31/66
29/70
42
18
20
20
43
18
17
22
43
17
19
21
15
20
34
5
17
13
44
6
17
14
44
1
74
80
76
Characteristic
Median age, years (range)
Primary tumor site, %
Oropharynx
Hypopharynx
Larynx
Oral cavity
TN stage (primary), %
T4 N0
T4 N1
T4 N2
T4 N3
Total T4 (N0/1/2/3), %
Hitt et al. ASCO 2009. Abstract 6009
Induction PF  CRT vs DPF  CRT vs CRT
Phase III Trial
Unresectable locally-advanced HNC
CRT
(N=119)
Total ICT
(DPF + PF)
(N=309)
Neutropenia
20
36
Febrile neutropenia
1
10
Thrombocytopenia
4
10
Asthenia
3
11
Mucositis
31
44
Radiation dermatitis
8
7
Grade 3/4 AEs,
% patients
* FN: 22% before (n=97) and 11% after (n=56) primary G-CSF amendment.
Hitt et al. ASCO 2009. Abstract 6009
Induction PF  CRT vs TPF  CRT vs CRT
Phase III Trial
Unresectable locally-advanced HNC
1.0
0.9
HR = 0.57; 95% CI, 0.45-0.74
p<0.0001
0.8
Primary endpoint: TTF
0.7
0.6
ICT + CRT
median 12.5 months
0.5
0.4
0.3
0.2
CRT
median 5.0 months
0.1
0.0
0
12
24
36
48
60
72
(months)
E
Number
of patients
at risk
157
96
N
234
119
120
36
78
26
48
17
26
11
10
4
Hitt et al. ASCO 2009. Abstract 6009
Induction PF  CRT vs TPF  CRT vs CRT
Phase III Trial
Unresectable locally-advanced HNC
Median
HR (95% CI)
vs CRT
TTF
(Months)
TTP
(Months)
OS
(Months)
CRT
(N=119)
Total ICT
(TPF + PF) (N=234)
5.0
12.5
0.57 (0.45-0.74)
13.1
18.5
0.79 (0.60-1.03)
27.1
37.1
0.85 (0.63-1.15)
Hitt et al. ASCO 2009. Abstract 6009
Induktionschemotherapie:
Patientenselektion
Patienten mit
 sehr gutem AZ
 sehr guter Compliance
 symptomatischer Tumorerkrankung
 wenn unmittelbare Remission erforderlich ist
 wenn Start der Radiotherapie verzögert ist
Risk factors for HPV
HPV pos
HPV neg
Total
tonsil
117 (48%)
37 (34%)
242
oropharynx
157 (45%)
118 (76%)
345
age
HPV pos
HPV neg
OR
< 55 yrs
21 (55%)
125 (52%)
3.4
> 55 yrs
17 (45%)
188 (54%)
1.0
Sexual
partners
HPV pos
HPV neg
OR
0-1
3 (10%)
40 (36%)
1.0
2-6
12 (41%)
38 (35%)
4.2
<6
14 (48%)
29 (26%)
6.4
Fakhry et al., ASCO 2007, Abstract 6000
Prognostic significance of HPV for patients with
HNSCC in a prospective, phase II trial (ECOG 2399)
Induction
chemotherapy
R
E
G
I
S
T
E
R
Paclitaxel 175 mg/m2
Carboplatin AUC 6
q 21 days
2 cycles
Concurrent
chemoradiation
R
E
S
P
O
N
S
E
RT 70 Gy / 35 fx / 7 weeks
Paclitaxel 30 mg/m2/week
R
E
S
P
O
N
S
E
Fakhry et al., ASCO 2007, Abstract 6000
Prognostic significance of HPV for patients with HNSCC in
a prospective, phase II trial (ECOG 2399)
HPV-pos
HPV-neg
P Value
Response
• Induction
• Protocol
82%
84%
55%
57%
.01
.07
2-Year PFS
86%
53%
.02
2-Year OS
95%
62%
.005
Survival, OP cancers
• 2-Year PFS
• 2-Year OS
85%
94%
50%
58%
.05
.004
Fakhry et al., ASCO 2007, Abstract 6000
Ergebnisse von Radiochemotherapie (RCT) oder
Induktionschemotherapie (IC) in Abhängigkeit von HVP
trial
patients regimen 2 yrs OS
2 yrs OS 2 yrs LCR 2 yrs LCR
HPV +
HPV -
HPV +
HPV -
ECOG 2399
62
IC+RCT
95%
62%
-
-
TAX 324
119
IC+RCT
90%
45%
-
-
RTOG 0129
323
RCT
88%
66%
86%
75%
RTOG 0202
185
RCT
91%
74%
93%
86%
Radiotherapy plus cetuximab for squamous-cell carcinoma
of the head and neck
RT (n=213)
Stage III and IV
non-metastatic
SCCHN
(n=424)
R
Stratified by
• Karnofsky PS
• Nodal involvement
• Tumor stage
• RT regimena
a
Investigators’ choice
Bonner et al. N Eng J Med 2006;354:567-578
ERBITUX + RT (n=211)
ERBITUX initial dose (400 mg/m2)
1 week before RT
ERBITUX (250 mg/m2)
+ RT (weeks 2–8)
ERBITUX + RT improves locoregional control
over RT alone in locally advanced SCCHN
Locoregional control (%)
Log-rank p=0.005
Hazard ratio
0.68 (CI: 0.52, 0.89)
100
80
60
40
+64%
20
locoregionäre
Kontrolle
14.9
24.4
20
30
0
0
10
40
50
60
Months
Bonner et al. N Eng J Med 2006;354:567-578
70
 ERBITUX + RT (n=211)
 RT alone (n=213)
ERBITUX + RT prolongs survival over RT alone
in locally advanced SCCHN
Probability of overall survival
ERBITUX + RT significantly improved long-term survival,
with nearly half of the patients alive at 5 years
1.0
0.9
5-year survival rate
RT
ERBITUX + RT
36%
46%
0.8
0.7
0.6
49.0
0.5
29.3
0.4
0.3
+67%
Gesamtüberleben
RT
ERBITUX + RT
0.2
p=0.018, HR=0.73 (0.56-0.95)
0.1
0
0
10
20
30
40
50
60
Time (months)
Bonner et al. N Eng J Med 2006;354:567-578; Bonner et al. Int J Radiat Oncol Biol Phys 2008;72(Suppl.1):e1–e4. Updated
information presented at ASTRO 2008
70
ERBITUX + RT in locally advanced SCCHN:
5-year update
Erbitux + RT improved survival independently of the tumor site
Primary tumor site
Oropharynx (n=253)
Larynx (n=108)
Hypopharynx (n=63)
0.0
0.6
1.2
1.8
Hazard ratio
Favors RT + ERBITUX
Favors RT alone
Erbitux + RT: Impact of skin rash on survival
Development of skin rash is associated with an additional survival benefit
1.00
Prominent rash, grade 2–4 (n=127)
0.90
Mild rash, grade 0/1 (n=81)
Overall survival
0.80
>68.8 months
0.70
0.60
0.50
25.6
months
0.40
0.30
0.20
0.10
p=0.002, HR=0.49 (0.34–0.72)
0
0
10
20
30
40
50
60
70
Time (months)
Bonner J et al. Lancet Oncology published online Nov 2009
Erbitux + RT:
Relevant grade > 3 adverse events
Bonner J et al. N Engl J Med 2006;354:567–578
Non-resectable SCCHN stage III & IV
ESMO guidelines 2009
Clinical recommendations for treatment
ESMO guidelines: recommendations for locally advanced non resectable
Level of
evidence
Grade of
recommendation
Concomitant Chemoradiotherapy
I
A
Erbitux + radiotherapy
I
A
sequential chemoradiotherapy
I
A
Treatment
Levels of evidence: from I to V, Level I being the highest level of evidence
Grades of recommendation: from A to D, Grade A being the highest grade of recommendation
L. Licitra & E. Felip On behalf of the ESMO Guidelines Working Group, Annals of Oncology 20 (Supplement 4): iv121–iv122, 2009