the integration and impact of modern radiotherapy ... · barker et al. ijrobp 59:960-970, 2004...
TRANSCRIPT
The Integration and Impact of
Modern Radiotherapy Techniques
in Clinical Practice
Kian Ang
Funding: P01-CA06294, R01-CA84415, GF Fletcher Chair,
Imclone (phase III trial)
From Bench to Bedside
Head and Neck Carcinoma
Track record in the development of:
Altered fractionation regimens
Concurrent radiation-chemotherapy
Biological Basis of Altered Fractionation
Hyperfractionation Accelerated Fractionation
Integration of lab research with clinical analyses
Differential Fractionation Effect
Withers et al.,
1988
Thames et al.,
1982
Clonogen Repopulation
Supra-Additive Effect of RT + Cisplatin
Bartelink et al.,
1986 Cisplatin
RT (4 Gy x 5) – if additive
Supra-Additive
Observed
Altered Fractionation & Radio-chemotherapy
Overall Survival
*Relative to Conventional Radiotherapy 1Bourhis et al., Lancet 2006; 2Pignon & Bourhis, Multidiscipl. H&N Meeting, 2007
Altered Fractionation (N=6,515)1
Hyperfractionation
Accelerated Fx - Dose
- Dose
Radio-chemotherapy (N=17,493)2
Adjuvant
Neoadjuvant
Concurrent
Cisplatin w/o FU (N=2,664)
Therapy Modality
< 0.0001
NS
NS
< 0.0001
p
4.1 %
2.3 %
2.2 %
6.9 %
9.6%
Absolute benefit at 5 years*
Risk Reduction*
10 %
2 %
5 %
19 %
24%
3.4 %
8.2 %
1.7 %
2.0 %
8 %
22 %
6 %
3 %
0.003
0.02 (HF vs. AF)
Efficacy ~ Toxicity of Radio-Chemotherapy S
ub
jects
(%
)
0
20
40
60
80 RT alone (n=231)
Combined RT + cisplatin (n=228)
p<0.001
Cooper JS, et al. N Engl J Med 350:1937, 2004
Research Directions (M0 Patients)
Biologic Targeting: signaling pathway
pattern of relapse
NT Protection &
Symptom Management: use of KGF
Tumor Control Toxicity
Topographic Targeting: IMRT - IGRT
IMRT
A method to shape
dose distributions to target volumes
with optimized non-uniform beam intensities
2700
3050 00
1450 2150
550
900
IMRT: Biologic Rationale
Isodose Shaping
NT Volume in High-Dose Region
Multiple Portals
Dose/F
(Outside GTV)
NT Tolerance
Toxicity ( QOL) Tumor Control
Therapy
Intensification
IMRT for Head and Neck Cancer MDACC
Oropharyngeal carcinomas
Nasopharyngeal carcinomas
Sinonasal cancers
Thyroid neoplasms
IMRT for Oropharynx Cancer
2000-June 2004: 259 patients
Age: 30-84 (54) years; 85% male
Site: tonsil-49%; tongue base-43%
T1-2(x): 220; T3-4: 39; N+: 225
Chemotherapy: 62 (T3-4 or N2-3)
3-Y local control: 94%
3-Y overall survival: 88%
Garden et al., ASTRO 2006
RTOG 0022 – ASTRO 2006
A Eisbruch, J Harris, A Garden, C Chao, W Straube,
C Schultz, G Sanguineti, C Jones, W Bosch, K Ang
Study population: 67 patients (14 centers)
Tumor: tongue base-20 (39%),
tonsil-33 (49%), soft palate 8 (12%)
Stage: T1-25%, T2-75%; N0-57%, N1-43%
Median follow-up: 1.6 (0.2-3.8) years
LR progression: 3 patients (4.9%)
No metastatic disease observed
Training & QA Procedures
IMRT is integrated into ongoing & new protocols
Credentialing - H&N Atlas - Online Review
ATC Advanced Technology Consortium
Protocol
CTV63 CTV56
IMRT ± Chemotherapy for NPC Progression-Free: Local & Regional
80 70 60 50 40 30 20 10 0 0
10
20
30
40
50
60
70
80
90
100
N= 87
Median FU=30 months
Length of Follow Up
Perc
en
t
Lee et al (UCSF), IJROBP, 53:1:12-21
5-Y nodal control: 97%
5-Y primary tumor control: 94%
5-Y metastasis-free: 66%
Recovery of Saliva Flow (A vs C)
p < 0.0001 0.0001 0.0001
Kam et al., ASCO 2005 (NPC)
IMRT
Non-
IMRT
Adaptive Radiotherapy - Anatomic Changes 19 CT Scans over 47 Days
Elapsed
Days
Barker et al. IJROBP 59:960-970, 2004 (MDACC); Lei Dong et al. (MDACC)
Patient Immobilized with Acquaplast Mask CTs Aligned Using BBs on Mask
Dosimetric Impact of Anatomic Changes
Original Plan Four Weeks Later (Mapped back to
the original planning CT using
deformable registration)
26Gy
Lei Dong et al. (MDACC)
Targeted Therapy
Topographic Targeting
IMRT
Biologic Targeting
Perturbed
Signaling Pathway
EGFR
EGFR vs Tumor Response (Rodent Models)
OCa OCa -I -I HCa HCa -I -I MCa MCa -K -K MCa MCa -4 -4 MCa MCa -35 -35 MCa MCa -29 -29 SCC-IV SCC-IV SCC-VII SCC-VII ACa ACa -SG -SG
0 5 10 15 20 25
TCD
50 (G
y)
40
50
60
70
80
90
Akimoto et al., Clin Cancer Res, 1999
Tu
mo
r C
ure
Do
se
(G
y)
EGFR Densitometric Value
r=0.8, p<0.01
Single Dose
0.001
0.01
0.1
1
0 2 4 6 8
Radiation Dose (Gy)
Su
rviv
ing
Fra
cti
on
OCA-I (Low EGFR)
EGFR vs Radiosensitivity
Clone 5-EGFR
Clone 1-neo
Liang et et., IJROBP, 2003
EGFR Expression vs Survival %
A L
I
V E
0
25
50
75
100
0 1 2 3 4 5 Years from Randomization
p=0.0006
Overall Survival
n=155 EGFR > Median
EGFR Median
%
A L
I V
E
N E
D
Years from Randomization
0
25
50
75
100
0 1 2 3 4 5
Disease-Free Survival
p=0.0016
n=155 EGFR > Median
EGFR Median
Ang et al., Cancer Research 62: 7350, 2002
EGFR Expression vs Pattern of Failure
Local-Regional Relapse
%
F A
I L
E D
Years from Randomization
0
25
50
75
100
0 1 2 3 4 5
EGFR > Median
EGFR Median
p=0.003
n=155
Distant Metastasis
%
W I T
H
M E
T S
0
25
50
75
100
Years from Randomization
0 1 2 3 4 5
p=0.96
n=155
EGFR > Median
EGFR Median
Ang et al., Cancer Research 62: 7350, 2002
A Phase III Study of
High Dose Radiotherapy ± Cetuximab (C225)
354:567-78, 2006
A Phase III Study of Radiotherapy ± Cetuximab
(C225) in Patients with Locally Advanced HNSCC
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 6 12 18 24 30 36 42 48 54 60 66
Pro
po
rtio
n
Months
Patients
Median
1-Year
2-Year
Log rank p= 0.005
RT+C
211
24 m
63%
50%
RT
213
15 m
55%
41%
RT + Cetuximab
RT Alone
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 6 12 18 24 30 36 42 48 54 60 66
Months
Patients
Events
Median
2-Year
3-Year
Log rank p= 0.03
RT+C
211
101
49 m
62%
56%
RT
213
121
29 m
55%
45%
RT + Cetuximab
RT Alone
Bonner et al., NEJM, 2006
Local-Regional Control
HR: 0.68 (0.52 - 0.89)
Survival HR = 0.74 (0.57 - 0.97)
No impact
on DM
34** 97* 18 91 Skin reaction
3* 14** – 2 Infusion reaction#
23 85 18 90 Radiation Dermatitis
A Phase III Study of Radiotherapy ± Cetuximab
in Patients with Locally Advanced SCCHN
*p < 0.05, ** p < 0.001, Fisher’s exact test. # Listed as related to cetuximab
25 64 30 63 Dysphagia
54 91 52 93 Mucositis/Stomatitis
4 52 5 50 Fatigue/Malaise
4 64 3 70 Xerostomia
Gr. 3/4 All Gr. Gr. 3/4 All Gr. % Toxicity
RT+C (N=208) RT (N=212)
Lessons
Excitement: validation of the concept that
targeting a perturbed signaling pathway
can selectively sensitize tumor to RT
Clinical challenges:
Cetuximab benefits 10-15% of patients
LR relapse still occurs in >50% of patients
Integrate cetuximab with RT + chemotherapy
Interpret findings in broad clinical context
Stage III & IV* SCC of:
• Oropharynx
• Hypopharynx
• Larynx
Stratify :
• Larynx ~ Others
• N0~N1,2a,2b~N2c-3
• KPS
60-80 ~ 90-100
• 3-D vs IMRT
• Pre-Rx PET (yes/no)
Integrating Cetuximab with RT+Chemotherapy
RTOG Phase III Trial (0522), PI: K. Ang, N: 720
R
A
N
D
O
M
I
Z
E *Exclude T1 any N
or T2N1
1. Accelerated FX* +
CDDP: 100 mg/m2, q3W X 2
2.
Accelerated FX* +
CDDP: 100 mg/m2, q3W X 2
C225: 400 mg/m2, Pre-RT, then
250 mg/m2/w x 7
RTOG H-0234: Locally Advanced Resected Randomized Phase II, PI: P. Harari, N: >240
R
A
N
D
O
M
I
Z
E
Surgical
Resection
High Risk
3-D vs IMRT
RT + C225 (400 250 mg/m2, qW)
+ DDP (30 mg/m2, qW)
RT + C225 (400 250 mg/m2, qW)
+ Docetaxel (15 mg/m2, qW)
Days after Radiation
Tu
mo
r S
ize (
mm
)
0 10 20 30 40 50 4
6
8
10
12
14
16 Control
A431
10 Gy 10 Gy + Doc
10 Gy + C225
10 Gy + C225 + Doc
Research Directions (M0 Patients)
Biologic Targeting: signaling pathway
pattern of relapse
NT Protection &
Symptom Management: use of KGF
Tumor Control Toxicity
Topographic Targeting: IMRT - IGRT
IMRT ± Chemotherapy for NPC
Center N Stage FU (mo)
LC DM-Free
Bucci IJROBP,
2004(abs)
118 50%
T3-4 30 96% 72%
(4-year data)
Kam IJROBP,
2004
63
51%
T3-4 29 92% 79%
(3-year data)
Wolden IJROBP,
2005
74 51%
T3-4 35 91% 78%
(3-year data)
RCTs Bevacizumab + Chemotherapy
Hurwitz NEJM 2004; Sandler ASCO 2005; Miller ASCO 2005
Prelim:
HR=0.674
11.0 6.1 28.2 14.2 715 15 mg/kg
q2w
Breast
12.5 10.2 6.4 4.5 27 10 878 15 mg/kg
q3w
NSCLC
20.3 15.6 10.6 6.2 44.8 34.8 813 5 mg/kg
q2w
Colorectal
CT +
BV
CT CT +
BV
CT CT +
BV
CT
m-OS
(months)
m-PFS
(months)
Response
Rate (%)
#
Pts.
BV
dose
Tumor
Type
R
E
G
I
S
T
E
R
NPC – RTOG 0615 (Phase II, PI: N. Lee)
T≥2b or N+
Type: WHO I-III
Concurrent:
IMRT (70 Gy)
CDDP (100mg/m2) x 3 cycles q 3 W
BV 15mg/kg q 3W
Adjuvant:
CDDP (80 mg/m2)
5FU (1000 mg/m2) x 3 cycles q 3W
BV 15mg/kg q3W
PORT ± Cisplatin for HNC
Patients with ECE and/or Margin+
% S
UR
VIV
ING
0
25
50
75
100
YEARS
0 1 2 3 4 5
EORTC 22931*
p= 0.019
RT+DDP
RT Alone
0
25
50
75
100
YEARS
0 1 2 3 4 5
RTOG 9501+
p= 0.063
RT+DDP
RT Alone
+Cooper et al., NEJM, 2004; *Bernier et al., NEJM, 2004; Bernier et al., Head Neck, 2005
PoRT for H & N CANCER: Survival vs Risk Grouping
Ang, Trotti, Brown et al., IJROBP, 2001
0 Gy
57.6 Gy
63 Gy
5-Y LRC: 68%
5-Y DM: 33%
ras
MEK
EGFR
Cyclin D1
Proliferation
VEGF
Endothelial cell Cancer cell
TGF
KDR
ZD6474
Endothelial cell proliferation
ZD6474: A Oral Dual EGFR-VEGFR TKI
Wedge SR, et al. Cancer Res 2002;62:4645–4655
RT
ZD6474 + RT
CONTROL
ZD6474
Lt Rt
Effect of ZD6474 and RT on Lung Adenocarcinoma
Courtesy:
M. O’Reilly
RT ± Paclitaxel (PTX) or ZD6474
RTOG 0619: Post-op Adjuvant
Phase II(R) in Planning, PI: David Raben
R
A
N
D
O
M
I
Z
E
Surgical
Resection
High Risk
RT + DDP (30 mg/m2, qW)
RT + DDP (30 mg/m2, qW)
+ ZD6474 (300 mg daily)
Research Directions
Biologic Targeting: signaling pathway
pattern of relapse
Normal Tissue Protection: use of growth factors
Tumor Control Toxicity
Topographic Targeting: IMRT - IGRT
Grade 4 Mucositis
KGF – Palifermin (Kepivance®)
FGF family (FGF-7) paracrine effector
Binds to KGFR, only on epithelial cells
Specific stimulatory activity for
epithelial cells (unlike other FGFs) proliferation
differentiation
survival
Rhu-KGF: N-terminal truncated version
of endogenous KGF to improve
stability
Water-soluble 16.3 kDa protein
Produced in E. coli FGF: Fibroblast growth factor.
Finch PW, et al. Science 245:752, 1989
Farrell CL, et al. Cancer Res 58:933, 1998
Pre-palifermin H&E 24 hr post-palifermin
(40 µg/kg/day for 3 days) H&E
Palifermin - biological activity in human buccal mucosa
H&E = hematoxylin and eosin
Effect of Palifermin (rHuKGF) on Mucositis Patients Undergoing TBI + CTH + AuBMT (Phase III)
Placebo
Palifermin
Placebo
= single IV dose of study drug (60 mcg/kg/d palifermin or placebo)
End of study
Ran
do
miz
ati
on
Day –11 –8 –4 –2 0 28
12 Gy in 3-4 days
Cyclophosphamide: 100 mg/kg
G-CSF until engraftment f T B I
Autologous
PBPC infusion
VP-16: 60 mg/kg
PBPC: Peripheral blood progenitor cell. Stratification by center and hematologic malignancy type
Adapted from Spielberger R, NEJM 351:2590-2598, 2004
Palifermin
Effect of Palifermin (rHuKGF) on Mucositis
Patients Undergoing TBI + CTH + AuBMT (Phase III)
Grade 4 Mucositis
20%
62%
Incid
en
ce (
%)
100
90
80
70
60
50
40
30
20
10
0
p < 0.001
Placebo Paliferminn = 106 n = 106
20%
62%
Incid
en
ce (
%)
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
p < 0.001
Placebo Paliferminn = 106 n = 106
Placebo Paliferminn = 106 n = 106
10.4
3.7
0
2
4
6
8
10
12
Me
an
Du
rati
on
(D
ays
)
Placebo(n = 106)
Palifermin(n = 106)
p < 0.001
(95% CI)
6.7d (5.3, 8.0)
10.4
3.7
0
2
4
6
8
10
12
0
2
4
6
8
10
12
Me
an
Du
rati
on
(D
ays
)
Placebo(n = 106)
Palifermin(n = 106)
p < 0.001
(95% CI)
6.7d (5.3, 8.0)
Adapted from Spielberger R, NEJM 351:2590-2598, 2004
RTOG 0435: KGF in Reducing Mucositis Phase III Trial, PI: D. Rosenthal
Sc
ree
nin
g
Ra
nd
om
iza
tio
n
If ulcerative OM
at week 7
Palifermin
Placebo
RT x 70Gy/7 weeks*
CDDP 100 mg/m2 x 3
*IMRT or 3D-RT allowed
Study Duration: Assess
2x/w during & after RT
until mucositis resolves to
WHO ≤ grade 1 or 8
weeks after RT
Summary - Opportunities & Challenges
Significant progress in H&N oncology
Optimize precision radiotherapy
Develop novel combined therapy by
perturbed signaling pathway (EGFR) –
validated the proof of principle
relapse pattern - ongoing
individual tumor features – high priority
Find strategy to reduce mucositis
The Integration and Impact of
Modern Radiotherapy Techniques
in Clinical Practice
Kian Ang
Funding: P01-CA06294, R01-CA84415, GF Fletcher Chair,
Imclone (phase III trial)
From Bench to Bedside
Head and Neck Carcinoma
Track record in the development of:
Altered fractionation regimens
Concurrent radiation-chemotherapy
Biological Basis of Altered Fractionation
Hyperfractionation Accelerated Fractionation
Integration of lab research with clinical analyses
Differential Fractionation Effect
Withers et al.,
1988
Thames et al.,
1982
Clonogen Repopulation
Supra-Additive Effect of RT + Cisplatin
Bartelink et al.,
1986 Cisplatin
RT (4 Gy x 5) – if additive
Supra-Additive
Observed
Altered Fractionation & Radio-chemotherapy
Overall Survival
*Relative to Conventional Radiotherapy 1Bourhis et al., Lancet 2006; 2Pignon & Bourhis, Multidiscipl. H&N Meeting, 2007
Altered Fractionation (N=6,515)1
Hyperfractionation
Accelerated Fx - Dose
- Dose
Radio-chemotherapy (N=17,493)2
Adjuvant
Neoadjuvant
Concurrent
Cisplatin w/o FU (N=2,664)
Therapy Modality
< 0.0001
NS
NS
< 0.0001
p
4.1 %
2.3 %
2.2 %
6.9 %
9.6%
Absolute benefit at 5 years*
Risk Reduction*
10 %
2 %
5 %
19 %
24%
3.4 %
8.2 %
1.7 %
2.0 %
8 %
22 %
6 %
3 %
0.003
0.02 (HF vs. AF)
From Bench to Bedside
Head and Neck Carcinoma
Track record in the development of:
Altered fractionation regimens
Concurrent radiation-chemotherapy
Biological Basis of Altered Fractionation
Hyperfractionation Accelerated Fractionation
Integration of lab research with clinical analyses
Differential Fractionation Effect
Withers et al.,
1988
Thames et al.,
1982
Clonogen Repopulation
Supra-Additive Effect of RT + Cisplatin
Bartelink et al.,
1986 Cisplatin
RT (4 Gy x 5) – if additive
Supra-Additive
Observed
Altered Fractionation & Radio-chemotherapy
Overall Survival
*Relative to Conventional Radiotherapy 1Bourhis et al., Lancet 2006; 2Pignon & Bourhis, Multidiscipl. H&N Meeting, 2007
Altered Fractionation (N=6,515)1
Hyperfractionation
Accelerated Fx - Dose
- Dose
Radio-chemotherapy (N=17,493)2
Adjuvant
Neoadjuvant
Concurrent
Cisplatin w/o FU (N=2,664)
Therapy Modality
< 0.0001
NS
NS
< 0.0001
p
4.1 %
2.3 %
2.2 %
6.9 %
9.6%
Absolute benefit at 5 years*
Risk Reduction*
10 %
2 %
5 %
19 %
24%
3.4 %
8.2 %
1.7 %
2.0 %
8 %
22 %
6 %
3 %
0.003
0.02 (HF vs. AF)
Efficacy ~ Toxicity of Radio-Chemotherapy S
ub
jects
(%
)
0
20
40
60
80 RT alone (n=231)
Combined RT + cisplatin (n=228)
p<0.001
Cooper JS, et al. N Engl J Med 350:1937, 2004
Research Directions (M0 Patients)
Biologic Targeting: signaling pathway
pattern of relapse
NT Protection &
Symptom Management: use of KGF
Tumor Control Toxicity
Topographic Targeting: IMRT - IGRT
IMRT
A method to shape
dose distributions to target volumes
with optimized non-uniform beam intensities
2700
3050 00
1450 2150
550
900
IMRT: Biologic Rationale
Isodose Shaping
NT Volume in High-Dose Region
Multiple Portals
Dose/F
(Outside GTV)
NT Tolerance
Toxicity ( QOL) Tumor Control
Therapy
Intensification
IMRT for Head and Neck Cancer MDACC
Oropharyngeal carcinomas
Nasopharyngeal carcinomas
Sinonasal cancers
Thyroid neoplasms
IMRT for Oropharynx Cancer
2000-June 2004: 259 patients
Age: 30-84 (54) years; 85% male
Site: tonsil-49%; tongue base-43%
T1-2(x): 220; T3-4: 39; N+: 225
Chemotherapy: 62 (T3-4 or N2-3)
3-Y local control: 94%
3-Y overall survival: 88%
Garden et al., ASTRO 2006
RTOG 0022 – ASTRO 2006
A Eisbruch, J Harris, A Garden, C Chao, W Straube,
C Schultz, G Sanguineti, C Jones, W Bosch, K Ang
Study population: 67 patients (14 centers)
Tumor: tongue base-20 (39%),
tonsil-33 (49%), soft palate 8 (12%)
Stage: T1-25%, T2-75%; N0-57%, N1-43%
Median follow-up: 1.6 (0.2-3.8) years
LR progression: 3 patients (4.9%)
No metastatic disease observed
Training & QA Procedures
IMRT is integrated into ongoing & new protocols
Credentialing - H&N Atlas - Online Review
ATC Advanced Technology Consortium
Protocol
CTV63 CTV56
IMRT ± Chemotherapy for NPC Progression-Free: Local & Regional
80 70 60 50 40 30 20 10 0 0
10
20
30
40
50
60
70
80
90
100
N= 87
Median FU=30 months
Length of Follow Up
Perc
en
t
Lee et al (UCSF), IJROBP, 53:1:12-21
5-Y nodal control: 97%
5-Y primary tumor control: 94%
5-Y metastasis-free: 66%
Recovery of Saliva Flow (A vs C)
p < 0.0001 0.0001 0.0001
Kam et al., ASCO 2005 (NPC)
Impact on QOL parameters was less obvious
IMRT
Non-
IMRT
Adaptive Radiotherapy - Anatomic Changes 19 CT Scans over 47 Days
Elapsed
Days
Barker et al. IJROBP 59:960-970, 2004 (MDACC); Lei Dong et al. (MDACC)
Patient Immobilized with Acquaplast Mask CTs Aligned Using BBs on Mask
Dosimetric Impact of Anatomic Changes
Original Plan Four Weeks Later (Mapped back to
the original planning CT using
deformable registration)
26Gy
Lei Dong et al. (MDACC)
Targeted Therapy
Topographic Targeting
IMRT
Biologic Targeting
Perturbed
Signaling Pathway
EGFR
EGFR vs Tumor Response (Rodent Models)
OCa OCa -I -I HCa HCa -I -I MCa MCa -K -K MCa MCa -4 -4 MCa MCa -35 -35 MCa MCa -29 -29 SCC-IV SCC-IV SCC-VII SCC-VII ACa ACa -SG -SG
0 5 10 15 20 25
TCD
50 (G
y)
40
50
60
70
80
90
Akimoto et al., Clin Cancer Res, 1999
Tu
mo
r C
ure
Do
se
(G
y)
EGFR Densitometric Value
r=0.8, p<0.01
Single Dose
0.001
0.01
0.1
1
0 2 4 6 8
Radiation Dose (Gy)
Su
rviv
ing
Fra
cti
on
OCA-I (Low EGFR)
EGFR vs Radiosensitivity
Clone 5-EGFR
Clone 1-neo
Liang et et., IJROBP, 2003
EGFR Expression vs Survival %
A L
I
V E
0
25
50
75
100
0 1 2 3 4 5 Years from Randomization
p=0.0006
Overall Survival
n=155 EGFR > Median
EGFR Median
%
A L
I V
E
N E
D
Years from Randomization
0
25
50
75
100
0 1 2 3 4 5
Disease-Free Survival
p=0.0016
n=155 EGFR > Median
EGFR Median
Ang et al., Cancer Research 62: 7350, 2002
EGFR Expression vs Pattern of Failure
Local-Regional Relapse
%
F A
I L
E D
Years from Randomization
0
25
50
75
100
0 1 2 3 4 5
EGFR > Median
EGFR Median
p=0.003
n=155
Distant Metastasis
%
W I T
H
M E
T S
0
25
50
75
100
Years from Randomization
0 1 2 3 4 5
p=0.96
n=155
EGFR > Median
EGFR Median
Ang et al., Cancer Research 62: 7350, 2002
A Phase III Study of
High Dose Radiotherapy ± Cetuximab (C225)
354:567-78, 2006
A Phase III Study of Radiotherapy ± Cetuximab
(C225) in Patients with Locally Advanced HNSCC
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 6 12 18 24 30 36 42 48 54 60 66
Pro
po
rtio
n
Months
Patients
Median
1-Year
2-Year
Log rank p= 0.005
RT+C
211
24 m
63%
50%
RT
213
15 m
55%
41%
RT + Cetuximab
RT Alone
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 6 12 18 24 30 36 42 48 54 60 66
Months
Patients
Events
Median
2-Year
3-Year
Log rank p= 0.03
RT+C
211
101
49 m
62%
56%
RT
213
121
29 m
55%
45%
RT + Cetuximab
RT Alone
Bonner et al., NEJM, 2006
Local-Regional Control
HR: 0.68 (0.52 - 0.89)
Survival HR = 0.74 (0.57 - 0.97)
No impact
on DM
34** 97* 18 91 Skin reaction
3* 14** – 2 Infusion reaction#
23 85 18 90 Radiation Dermatitis
A Phase III Study of Radiotherapy ± Cetuximab
in Patients with Locally Advanced SCCHN
*p < 0.05, ** p < 0.001, Fisher’s exact test. # Listed as related to cetuximab
25 64 30 63 Dysphagia
54 91 52 93 Mucositis/Stomatitis
4 52 5 50 Fatigue/Malaise
4 64 3 70 Xerostomia
Gr. 3/4 All Gr. Gr. 3/4 All Gr. % Toxicity
RT+C (N=208) RT (N=212)
Lessons
Excitement: validation of the concept that
targeting a perturbed signaling pathway
can selectively sensitize tumor to RT
Clinical challenges:
Cetuximab benefits 10-15% of patients
LR relapse still occurs in >50% of patients
Integrate cetuximab with RT + chemotherapy
Interpret findings in broad clinical context
Stage III & IV* SCC of:
• Oropharynx
• Hypopharynx
• Larynx
Stratify :
• Larynx ~ Others
• N0~N1,2a,2b~N2c-3
• KPS
60-80 ~ 90-100
• 3-D vs IMRT
• Pre-Rx PET (yes/no)
Integrating Cetuximab with RT+Chemotherapy
RTOG Phase III Trial (0522), PI: K. Ang, N: 720
R
A
N
D
O
M
I
Z
E *Exclude T1 any N
or T2N1
1. Accelerated FX* +
CDDP: 100 mg/m2, q3W X 2
2.
Accelerated FX* +
CDDP: 100 mg/m2, q3W X 2
C225: 400 mg/m2, Pre-RT, then
250 mg/m2/w x 7
RTOG H-0234: Locally Advanced Resected Randomized Phase II, PI: P. Harari, N: >240
R
A
N
D
O
M
I
Z
E
Surgical
Resection
High Risk
3-D vs IMRT
RT + C225 (400 250 mg/m2, qW)
+ DDP (30 mg/m2, qW)
RT + C225 (400 250 mg/m2, qW)
+ Docetaxel (15 mg/m2, qW)
Days after Radiation
Tu
mo
r S
ize (
mm
)
0 10 20 30 40 50 4
6
8
10
12
14
16 Control
A431
10 Gy 10 Gy + Doc
10 Gy + C225
10 Gy + C225 + Doc
Research Directions (M0 Patients)
Biologic Targeting: signaling pathway
pattern of relapse
NT Protection &
Symptom Management: use of KGF
Tumor Control Toxicity
Topographic Targeting: IMRT - IGRT
IMRT ± Chemotherapy for NPC
Center N Stage FU (mo)
LC DM-Free
Bucci IJROBP,
2004(abs)
118 50%
T3-4 30 96% 72%
(4-year data)
Kam IJROBP,
2004
63
51%
T3-4 29 92% 79%
(3-year data)
Wolden IJROBP,
2005
74 51%
T3-4 35 91% 78%
(3-year data)
RCTs Bevacizumab + Chemotherapy
Hurwitz NEJM 2004; Sandler ASCO 2005; Miller ASCO 2005
Prelim:
HR=0.674
11.0 6.1 28.2 14.2 715 15 mg/kg
q2w
Breast
12.5 10.2 6.4 4.5 27 10 878 15 mg/kg
q3w
NSCLC
20.3 15.6 10.6 6.2 44.8 34.8 813 5 mg/kg
q2w
Colorectal
CT +
BV
CT CT +
BV
CT CT +
BV
CT
m-OS
(months)
m-PFS
(months)
Response
Rate (%)
#
Pts.
BV
dose
Tumor
Type
R
E
G
I
S
T
E
R
NPC – RTOG 0615 (Phase II, PI: N. Lee)
T≥2b or N+
Type: WHO I-III
Concurrent:
IMRT (70 Gy)
CDDP (100mg/m2) x 3 cycles q 3 W
BV 15mg/kg q 3W
Adjuvant:
CDDP (80 mg/m2)
5FU (1000 mg/m2) x 3 cycles q 3W
BV 15mg/kg q3W
PORT ± Cisplatin for HNC
Patients with ECE and/or Margin+
% S
UR
VIV
ING
0
25
50
75
100
YEARS
0 1 2 3 4 5
EORTC 22931*
p= 0.019
RT+DDP
RT Alone
0
25
50
75
100
YEARS
0 1 2 3 4 5
RTOG 9501+
p= 0.063
RT+DDP
RT Alone
+Cooper et al., NEJM, 2004; *Bernier et al., NEJM, 2004; Bernier et al., Head Neck, 2005
PoRT for H & N CANCER: Survival vs Risk Grouping
Ang, Trotti, Brown et al., IJROBP, 2001
0 Gy
57.6 Gy
63 Gy
5-Y LRC: 68%
5-Y DM: 33%
ras
MEK
EGFR
Cyclin D1
Proliferation
VEGF
Endothelial cell Cancer cell
TGF
KDR
ZD6474
Endothelial cell proliferation
ZD6474: A Oral Dual EGFR-VEGFR TKI
Wedge SR, et al. Cancer Res 2002;62:4645–4655
RT
ZD6474 + RT
CONTROL
ZD6474
Lt Rt
Effect of ZD6474 and RT on Lung Adenocarcinoma
Courtesy:
M. O’Reilly
RT ± Paclitaxel (PTX) or ZD6474
RTOG 0619: Post-op Adjuvant
Phase II(R) in Planning, PI: David Raben
R
A
N
D
O
M
I
Z
E
Surgical
Resection
High Risk
RT + DDP (30 mg/m2, qW)
RT + DDP (30 mg/m2, qW)
+ ZD6474 (300 mg daily)
Research Directions
Biologic Targeting: signaling pathway
pattern of relapse
Normal Tissue Protection: use of growth factors
Tumor Control Toxicity
Topographic Targeting: IMRT - IGRT
Grade 4 Mucositis
KGF – Palifermin (Kepivance®)
FGF family (FGF-7) paracrine effector
Binds to KGFR, only on epithelial cells
Specific stimulatory activity for
epithelial cells (unlike other FGFs) proliferation
differentiation
survival
Rhu-KGF: N-terminal truncated version
of endogenous KGF to improve
stability
Water-soluble 16.3 kDa protein
Produced in E. coli FGF: Fibroblast growth factor.
Finch PW, et al. Science 245:752, 1989
Farrell CL, et al. Cancer Res 58:933, 1998
Pre-palifermin H&E 24 hr post-palifermin
(40 µg/kg/day for 3 days) H&E
Palifermin - biological activity in human buccal mucosa
H&E = hematoxylin and eosin
Effect of Palifermin (rHuKGF) on Mucositis
Patients Undergoing TBI + CTH + AuBMT (Phase III)
Grade 4 Mucositis
20%
62%
Incid
en
ce (
%)
100
90
80
70
60
50
40
30
20
10
0
p < 0.001
Placebo Paliferminn = 106 n = 106
20%
62%
Incid
en
ce (
%)
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
p < 0.001
Placebo Paliferminn = 106 n = 106
Placebo Paliferminn = 106 n = 106
10.4
3.7
0
2
4
6
8
10
12
Me
an
Du
rati
on
(D
ays
)
Placebo(n = 106)
Palifermin(n = 106)
p < 0.001
(95% CI)
6.7d (5.3, 8.0)
10.4
3.7
0
2
4
6
8
10
12
0
2
4
6
8
10
12
Me
an
Du
rati
on
(D
ays
)
Placebo(n = 106)
Palifermin(n = 106)
p < 0.001
(95% CI)
6.7d (5.3, 8.0)
Adapted from Spielberger R, NEJM 351:2590-2598, 2004
RTOG 0435: KGF in Reducing Mucositis Phase III Trial, PI: D. Rosenthal
Sc
ree
nin
g
Ra
nd
om
iza
tio
n
If ulcerative OM
at week 7
Palifermin
Placebo
RT x 70Gy/7 weeks*
CDDP 100 mg/m2 x 3
*IMRT or 3D-RT allowed
Study Duration: Assess
2x/w during & after RT
until mucositis resolves to
WHO ≤ grade 1 or 8
weeks after RT
Summary - Opportunities & Challenges
Significant progress in H&N oncology
Optimize precision radiotherapy
Develop novel combined therapy by
perturbed signaling pathway (EGFR) –
validated the proof of principle
relapse pattern - ongoing
individual tumor features – high priority
Find strategy to reduce mucositis