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