The Integration and Impact of Modern Radiotherapy Techniques in Clinical Practice. Kian Ang

Transcription

1 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)

2 From Bench to Bedside Head and Neck Carcinoma Track record in the development of: Altered fractionation regimens Concurrent radiation-chemotherapy

3 Biological Basis of Altered Fractionation Hyperfractionation Thames et al., 1982 Accelerated Fractionation Withers et al., 1988 Differential Fractionation Effect Clonogen Repopulation Integration of lab research with clinical analyses

4 Supra-Additive Effect of RT + Cisplatin Supra-Additive Observed RT (4 Gy x 5) if additive Cisplatin Bartelink et al., 1986

5 Altered Fractionation & Radio-chemotherapy Overall Survival Therapy Modality Absolute benefit at 5 years* Risk Reduction* p Altered Fractionation (N=6,515) 1 Hyperfractionation Accelerated Fx - Dose - Dose 3.4 % 8.2 % 1.7 % 2.0 % 8 % 22 % 6 % 3 % (HF vs. AF) Radio-chemotherapy (N=17,493) 2 Adjuvant Neoadjuvant Concurrent Cisplatin w/o FU (N=2,664) 4.1 % 2.3 % 2.2 % 6.9 % 9.6% 10 % 2 % 5 % 19 % 24% < NS NS < *Relative to Conventional Radiotherapy 1 Bourhis et al., Lancet 2006; 2 Pignon & Bourhis, Multidiscipl. H&N Meeting, 2007

6 Subjects (%) Efficacy ~ Toxicity of Radio-Chemotherapy RT alone (n=231) Combined RT + cisplatin (n=228) p< Cooper JS, et al. N Engl J Med 350:1937, 2004

7 Research Directions (M0 Patients) Topographic Targeting: IMRT - IGRT Tumor Control Toxicity Biologic Targeting: signaling pathway pattern of relapse NT Protection & Symptom Management: use of KGF

8 305 0 IMRT A method to shape dose distributions to target volumes with optimized non-uniform beam intensities

9 IMRT: Biologic Rationale Multiple Portals Isodose Shaping Dose/F (Outside GTV) NT Volume in High-Dose Region NT Tolerance Toxicity ( QOL) Tumor Control Therapy Intensification

10 IMRT for Head and Neck Cancer MDACC Oropharyngeal carcinomas Nasopharyngeal carcinomas Sinonasal cancers Thyroid neoplasms

11 IMRT for Oropharynx Cancer 2000-June 2004: 259 patients Age: (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

12 RTOG 0022 ASTRO 2006 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 ( ) years LR progression: 3 patients (4.9%) No metastatic disease observed A Eisbruch, J Harris, A Garden, C Chao, W Straube, C Schultz, G Sanguineti, C Jones, W Bosch, K Ang

13 Training & QA Procedures Credentialing - H&N Atlas - Online Review CTV 56 CTV 63 Protocol ATC Advanced Technology Consortium IMRT is integrated into ongoing & new protocols

14 Percent IMRT ± Chemotherapy for NPC Progression-Free: Local & Regional Y nodal control: 97% 5-Y primary tumor control: 94% 5-Y metastasis-free: 66% N= 87 Median FU=30 months Lee et al (UCSF), IJROBP, 53:1: Length of Follow Up

15 Recovery of Saliva Flow (A vs C) Kam et al., ASCO 2005 (NPC) Non- IMRT IMRT p <

16 Adaptive Radiotherapy - Anatomic Changes 19 CT Scans over 47 Days Elapsed Days Patient Immobilized with Acquaplast Mask CTs Aligned Using BBs on Mask Barker et al. IJROBP 59: , 2004 (MDACC); Lei Dong et al. (MDACC)

17 Dosimetric Impact of Anatomic Changes 26Gy Original Plan Lei Dong et al. (MDACC) Four Weeks Later (Mapped back to the original planning CT using deformable registration)

18 Targeted Therapy Biologic Targeting Perturbed Signaling Pathway Topographic Targeting IMRT EGFR

19 Tumor Cure Dose (Gy) EGFR vs Tumor Response (Rodent Models) OCa -I HCa -I MCa -29 MCa -35 MCa -4 MCa -K SCC-VII SCC-IV ACa -SG Akimoto et al., Clin Cancer Res, Single Dose TCD50 (Gy) r=0.8, p< EGFR Densitometric Value

20 Surviving Fraction EGFR vs Radiosensitivity 1 Clone 5-EGFR 0.1 Clone 1-neo 0.01 OCA-I (Low EGFR) Radiation Dose (Gy) Liang et et., IJROBP, 2003

21 % A L I V E EGFR Expression vs Survival Overall Survival Disease-Free Survival 100 p= p= n=155 EGFR Median EGFR > Median % A L I V E N E D EGFR Median 25 n=155 EGFR > Median Years from Randomization Years from Randomization Ang et al., Cancer Research 62: 7350, 2002

22 % F A I L E D % W I T H M E T S EGFR Expression vs Pattern of Failure Local-Regional Relapse Distant Metastasis 100 p= p= EGFR > Median EGFR Median 25 n=155 EGFR Median 0 n=155 EGFR > Median Years from Randomization Years from Randomization Ang et al., Cancer Research 62: 7350, 2002

23 A Phase III Study of High Dose Radiotherapy ± Cetuximab (C225) 354:567-78, 2006

24 Proportion A Phase III Study of Radiotherapy ± Cetuximab (C225) in Patients with Locally Advanced HNSCC Local-Regional Control HR: 0.68 ( ) Survival HR = 0.74 ( ) RT + Cetuximab 0.5 RT + Cetuximab RT m 55% RT+C m 63% 50% Patients Median 1-Year 2-Year 41% Log rank p= RT Alone RT Patients 213 RT+C 211 Events Median 29 m 49 m 2-Year 3-Year 55% 45% 62% 56% Log rank p= 0.03 RT Alone No impact on DM Months Bonner et al., NEJM, 2006 Months

25 A Phase III Study of Radiotherapy ± Cetuximab in Patients with Locally Advanced SCCHN % Toxicity RT (N=212) All Gr. Gr. 3/4 RT+C (N=208) All Gr. Gr. 3/4 Mucositis/Stomatitis Dysphagia Xerostomia Fatigue/Malaise Radiation Dermatitis Skin reaction * 34** Infusion reaction # 2 14** 3* *p < 0.05, ** p < 0.001, Fisher s exact test. # Listed as related to cetuximab

26 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

27 Integrating Cetuximab with RT+Chemotherapy RTOG Phase III Trial (0522), PI: K. Ang, N: 720 Stage III & IV* SCC of: Oropharynx Hypopharynx Larynx Stratify : Larynx ~ Others N0~N1,2a,2b~N2c-3 KPS ~ D vs IMRT Pre-Rx PET (yes/no) R A N D O M I Z Accelerated FX* + CDDP: 100 mg/m 2, q3w X 2 Accelerated FX* + CDDP: 100 mg/m 2, q3w X 2 C225: 400 mg/m 2, Pre-RT, then 250 mg/m 2 /w x 7 *Exclude T1 any N or T2N1 E

28 Tumor Size (mm) RTOG H-0234: Locally Advanced Resected Randomized Phase II, PI: P. Harari, N: >240 Surgical Resection High Risk 3-D vs IMRT R A N D O M I Z E RT + C225 ( mg/m 2, qw) + DDP (30 mg/m 2, qw) RT + C225 ( mg/m 2, qw) + Docetaxel (15 mg/m 2, qw) Control A Gy 10 Gy + Doc 10 Gy + C Gy + C225 + Doc Days after Radiation

29 Research Directions (M0 Patients) Topographic Targeting: IMRT - IGRT Tumor Control Toxicity Biologic Targeting: signaling pathway pattern of relapse NT Protection & Symptom Management: use of KGF

30 IMRT ± Chemotherapy for NPC Center N Stage FU (mo) LC DM-Free Bucci IJROBP, 2004(abs) % T % 72% (4-year data) Kam IJROBP, % T % 79% (3-year data) Wolden IJROBP, % 91% 78% 35 T3-4 (3-year data)

31 RCTs Bevacizumab + Chemotherapy Tumor Type BV dose # Pts. Response Rate (%) CT CT + BV m-pfs (months) CT CT + BV m-os (months) CT CT + BV Colorectal 5 mg/kg q2w NSCLC 15 mg/kg q3w Breast 15 mg/kg q2w Prelim: HR=0.674 Hurwitz NEJM 2004; Sandler ASCO 2005; Miller ASCO 2005

32 NPC RTOG 0615 (Phase II, PI: N. Lee) T 2b or N+ Type: WHO I-III R E G I S T E R Concurrent: IMRT (70 Gy) CDDP (100mg/m 2 ) x 3 cycles q 3 W BV 15mg/kg q 3W Adjuvant: CDDP (80 mg/m 2 ) 5FU (1000 mg/m 2 ) x 3 cycles q 3W BV 15mg/kg q3w

33 % SURVIVING PORT ± Cisplatin for HNC Patients with ECE and/or Margin+ 100 RTOG EORTC 22931* RT+DDP 50 RT+DDP 25 RT Alone 25 RT Alone 0 p= YEARS 0 p= YEARS + Cooper et al., NEJM, 2004; *Bernier et al., NEJM, 2004; Bernier et al., Head Neck, 2005

34 PoRT for H & N CANCER: Survival vs Risk Grouping 0 Gy 57.6 Gy 63 Gy 5-Y LRC: 68% 5-Y DM: 33% Ang, Trotti, Brown et al., IJROBP, 2001

35 ZD6474: A Oral Dual EGFR-VEGFR TKI EGFR TGF ZD6474 Cancer cell ras MEK VEGF Endothelial cell KDR Cyclin D1 Endothelial cell proliferation Proliferation Wedge SR, et al. Cancer Res 2002;62:

36 Effect of ZD6474 and RT on Lung Adenocarcinoma Rt Lt CONTROL RT Courtesy: M. O Reilly ZD6474 ZD RT

37 RT ± Paclitaxel (PTX) or ZD6474

38 RTOG 0619: Post-op Adjuvant Phase II(R) in Planning, PI: David Raben Surgical Resection High Risk R A N D O M I Z E RT + DDP (30 mg/m 2, qw) RT + DDP (30 mg/m2, qw) + ZD6474 (300 mg daily)

39 Research Directions Topographic Targeting: IMRT - IGRT Tumor Control Toxicity Biologic Targeting: signaling pathway pattern of relapse Normal Tissue Protection: use of growth factors

40 Grade 4 Mucositis

41 KGF Palifermin (Kepivance ) FGF: Fibroblast growth factor. Finch PW, et al. Science 245:752, 1989 Farrell CL, et al. Cancer Res 58:933, 1998 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

42 Palifermin - biological activity in human buccal mucosa Pre-palifermin H&E H&E = hematoxylin and eosin 24 hr post-palifermin (40 µg/kg/day for 3 days) H&E

43 Randomization Effect of Palifermin (rhukgf) on Mucositis Patients Undergoing TBI + CTH + AuBMT (Phase III) VP-16: 60 mg/kg 12 Gy in 3-4 days Cyclophosphamide: 100 mg/kg Autologous PBPC infusion f T B I G-CSF until engraftment End of study Day Placebo Palifermin Placebo Palifermin = single IV dose of study drug (60 mcg/kg/d palifermin or placebo) PBPC: Peripheral blood progenitor cell. Stratification by center and hematologic malignancy type Adapted from Spielberger R, NEJM 351: , 2004

44 Incidence (%) Mean Duration (Days) Effect of Palifermin (rhukgf) on Mucositis Patients Undergoing TBI + CTH + AuBMT (Phase III) Grade 4 Mucositis p < % 20% Placebo Palifermin n = 106 n = p < (95% CI) 6.7d (5.3, 8.0) 3.7 Placebo (n = 106) Adapted from Spielberger R, NEJM 351: , 2004 Palifermin (n = 106)

45 Screening Randomization RTOG 0435: KGF in Reducing Mucositis Phase III Trial, PI: D. Rosenthal If ulcerative OM at week 7 Palifermin Placebo RT x 70Gy/7 weeks* CDDP 100 mg/m 2 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

46 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

47 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)

48 From Bench to Bedside Head and Neck Carcinoma Track record in the development of: Altered fractionation regimens Concurrent radiation-chemotherapy

49 Biological Basis of Altered Fractionation Hyperfractionation Thames et al., 1982 Accelerated Fractionation Withers et al., 1988 Differential Fractionation Effect Clonogen Repopulation Integration of lab research with clinical analyses

50 Supra-Additive Effect of RT + Cisplatin Supra-Additive Observed RT (4 Gy x 5) if additive Cisplatin Bartelink et al., 1986

51 Altered Fractionation & Radio-chemotherapy Overall Survival Therapy Modality Absolute benefit at 5 years* Risk Reduction* p Altered Fractionation (N=6,515) 1 Hyperfractionation Accelerated Fx - Dose - Dose 3.4 % 8.2 % 1.7 % 2.0 % 8 % 22 % 6 % 3 % (HF vs. AF) Radio-chemotherapy (N=17,493) 2 Adjuvant Neoadjuvant Concurrent Cisplatin w/o FU (N=2,664) 4.1 % 2.3 % 2.2 % 6.9 % 9.6% 10 % 2 % 5 % 19 % 24% < NS NS < *Relative to Conventional Radiotherapy 1 Bourhis et al., Lancet 2006; 2 Pignon & Bourhis, Multidiscipl. H&N Meeting, 2007

52 From Bench to Bedside Head and Neck Carcinoma Track record in the development of: Altered fractionation regimens Concurrent radiation-chemotherapy

53 Biological Basis of Altered Fractionation Hyperfractionation Thames et al., 1982 Accelerated Fractionation Withers et al., 1988 Differential Fractionation Effect Clonogen Repopulation Integration of lab research with clinical analyses

54 Supra-Additive Effect of RT + Cisplatin Supra-Additive Observed RT (4 Gy x 5) if additive Cisplatin Bartelink et al., 1986

55 Altered Fractionation & Radio-chemotherapy Overall Survival Therapy Modality Absolute benefit at 5 years* Risk Reduction* p Altered Fractionation (N=6,515) 1 Hyperfractionation Accelerated Fx - Dose - Dose 3.4 % 8.2 % 1.7 % 2.0 % 8 % 22 % 6 % 3 % (HF vs. AF) Radio-chemotherapy (N=17,493) 2 Adjuvant Neoadjuvant Concurrent Cisplatin w/o FU (N=2,664) 4.1 % 2.3 % 2.2 % 6.9 % 9.6% 10 % 2 % 5 % 19 % 24% < NS NS < *Relative to Conventional Radiotherapy 1 Bourhis et al., Lancet 2006; 2 Pignon & Bourhis, Multidiscipl. H&N Meeting, 2007

56 Subjects (%) Efficacy ~ Toxicity of Radio-Chemotherapy RT alone (n=231) Combined RT + cisplatin (n=228) p< Cooper JS, et al. N Engl J Med 350:1937, 2004

57 Research Directions (M0 Patients) Topographic Targeting: IMRT - IGRT Tumor Control Toxicity Biologic Targeting: signaling pathway pattern of relapse NT Protection & Symptom Management: use of KGF

58 305 0 IMRT A method to shape dose distributions to target volumes with optimized non-uniform beam intensities

59 IMRT: Biologic Rationale Multiple Portals Isodose Shaping Dose/F (Outside GTV) NT Volume in High-Dose Region NT Tolerance Toxicity ( QOL) Tumor Control Therapy Intensification

60 IMRT for Head and Neck Cancer MDACC Oropharyngeal carcinomas Nasopharyngeal carcinomas Sinonasal cancers Thyroid neoplasms

61 IMRT for Oropharynx Cancer 2000-June 2004: 259 patients Age: (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

62 RTOG 0022 ASTRO 2006 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 ( ) years LR progression: 3 patients (4.9%) No metastatic disease observed A Eisbruch, J Harris, A Garden, C Chao, W Straube, C Schultz, G Sanguineti, C Jones, W Bosch, K Ang

63 Training & QA Procedures Credentialing - H&N Atlas - Online Review CTV 56 CTV 63 Protocol ATC Advanced Technology Consortium IMRT is integrated into ongoing & new protocols

64 Percent IMRT ± Chemotherapy for NPC Progression-Free: Local & Regional Y nodal control: 97% 5-Y primary tumor control: 94% 5-Y metastasis-free: 66% N= 87 Median FU=30 months Lee et al (UCSF), IJROBP, 53:1: Length of Follow Up

65 Recovery of Saliva Flow (A vs C) Kam et al., ASCO 2005 (NPC) Impact on QOL parameters was less obvious Non- IMRT IMRT p <

66 Adaptive Radiotherapy - Anatomic Changes 19 CT Scans over 47 Days Elapsed Days Patient Immobilized with Acquaplast Mask CTs Aligned Using BBs on Mask Barker et al. IJROBP 59: , 2004 (MDACC); Lei Dong et al. (MDACC)

67 Dosimetric Impact of Anatomic Changes 26Gy Original Plan Lei Dong et al. (MDACC) Four Weeks Later (Mapped back to the original planning CT using deformable registration)

68 Targeted Therapy Biologic Targeting Perturbed Signaling Pathway Topographic Targeting IMRT EGFR

69 Tumor Cure Dose (Gy) EGFR vs Tumor Response (Rodent Models) OCa -I HCa -I MCa -29 MCa -35 MCa -4 MCa -K SCC-VII SCC-IV ACa -SG Akimoto et al., Clin Cancer Res, Single Dose TCD50 (Gy) r=0.8, p< EGFR Densitometric Value

70 Surviving Fraction EGFR vs Radiosensitivity 1 Clone 5-EGFR 0.1 Clone 1-neo 0.01 OCA-I (Low EGFR) Radiation Dose (Gy) Liang et et., IJROBP, 2003

71 % A L I V E EGFR Expression vs Survival Overall Survival Disease-Free Survival 100 p= p= n=155 EGFR Median EGFR > Median % A L I V E N E D EGFR Median 25 n=155 EGFR > Median Years from Randomization Years from Randomization Ang et al., Cancer Research 62: 7350, 2002

72 % F A I L E D % W I T H M E T S EGFR Expression vs Pattern of Failure Local-Regional Relapse Distant Metastasis 100 p= p= EGFR > Median EGFR Median 25 n=155 EGFR Median 0 n=155 EGFR > Median Years from Randomization Years from Randomization Ang et al., Cancer Research 62: 7350, 2002

73 A Phase III Study of High Dose Radiotherapy ± Cetuximab (C225) 354:567-78, 2006

74 Proportion A Phase III Study of Radiotherapy ± Cetuximab (C225) in Patients with Locally Advanced HNSCC Local-Regional Control HR: 0.68 ( ) Survival HR = 0.74 ( ) RT + Cetuximab 0.5 RT + Cetuximab RT m 55% RT+C m 63% 50% Patients Median 1-Year 2-Year 41% Log rank p= RT Alone RT Patients 213 RT+C 211 Events Median 29 m 49 m 2-Year 3-Year 55% 45% 62% 56% Log rank p= 0.03 RT Alone No impact on DM Months Bonner et al., NEJM, 2006 Months

75 A Phase III Study of Radiotherapy ± Cetuximab in Patients with Locally Advanced SCCHN % Toxicity RT (N=212) All Gr. Gr. 3/4 RT+C (N=208) All Gr. Gr. 3/4 Mucositis/Stomatitis Dysphagia Xerostomia Fatigue/Malaise Radiation Dermatitis Skin reaction * 34** Infusion reaction # 2 14** 3* *p < 0.05, ** p < 0.001, Fisher s exact test. # Listed as related to cetuximab

76 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

77 Integrating Cetuximab with RT+Chemotherapy RTOG Phase III Trial (0522), PI: K. Ang, N: 720 Stage III & IV* SCC of: Oropharynx Hypopharynx Larynx Stratify : Larynx ~ Others N0~N1,2a,2b~N2c-3 KPS ~ D vs IMRT Pre-Rx PET (yes/no) R A N D O M I Z Accelerated FX* + CDDP: 100 mg/m 2, q3w X 2 Accelerated FX* + CDDP: 100 mg/m 2, q3w X 2 C225: 400 mg/m 2, Pre-RT, then 250 mg/m 2 /w x 7 *Exclude T1 any N or T2N1 E

78 Tumor Size (mm) RTOG H-0234: Locally Advanced Resected Randomized Phase II, PI: P. Harari, N: >240 Surgical Resection High Risk 3-D vs IMRT R A N D O M I Z E RT + C225 ( mg/m 2, qw) + DDP (30 mg/m 2, qw) RT + C225 ( mg/m 2, qw) + Docetaxel (15 mg/m 2, qw) Control A Gy 10 Gy + Doc 10 Gy + C Gy + C225 + Doc Days after Radiation

79 Research Directions (M0 Patients) Topographic Targeting: IMRT - IGRT Tumor Control Toxicity Biologic Targeting: signaling pathway pattern of relapse NT Protection & Symptom Management: use of KGF

80 IMRT ± Chemotherapy for NPC Center N Stage FU (mo) LC DM-Free Bucci IJROBP, 2004(abs) % T % 72% (4-year data) Kam IJROBP, % T % 79% (3-year data) Wolden IJROBP, % 91% 78% 35 T3-4 (3-year data)

81 RCTs Bevacizumab + Chemotherapy Tumor Type BV dose # Pts. Response Rate (%) CT CT + BV m-pfs (months) CT CT + BV m-os (months) CT CT + BV Colorectal 5 mg/kg q2w NSCLC 15 mg/kg q3w Breast 15 mg/kg q2w Prelim: HR=0.674 Hurwitz NEJM 2004; Sandler ASCO 2005; Miller ASCO 2005

82 NPC RTOG 0615 (Phase II, PI: N. Lee) T 2b or N+ Type: WHO I-III R E G I S T E R Concurrent: IMRT (70 Gy) CDDP (100mg/m 2 ) x 3 cycles q 3 W BV 15mg/kg q 3W Adjuvant: CDDP (80 mg/m 2 ) 5FU (1000 mg/m 2 ) x 3 cycles q 3W BV 15mg/kg q3w

83 % SURVIVING PORT ± Cisplatin for HNC Patients with ECE and/or Margin+ 100 RTOG EORTC 22931* RT+DDP 50 RT+DDP 25 RT Alone 25 RT Alone 0 p= YEARS 0 p= YEARS + Cooper et al., NEJM, 2004; *Bernier et al., NEJM, 2004; Bernier et al., Head Neck, 2005

84 PoRT for H & N CANCER: Survival vs Risk Grouping 0 Gy 57.6 Gy 63 Gy 5-Y LRC: 68% 5-Y DM: 33% Ang, Trotti, Brown et al., IJROBP, 2001

85 ZD6474: A Oral Dual EGFR-VEGFR TKI EGFR TGF ZD6474 Cancer cell ras MEK VEGF Endothelial cell KDR Cyclin D1 Endothelial cell proliferation Proliferation Wedge SR, et al. Cancer Res 2002;62:

86 Effect of ZD6474 and RT on Lung Adenocarcinoma Rt Lt CONTROL RT Courtesy: M. O Reilly ZD6474 ZD RT

87 RT ± Paclitaxel (PTX) or ZD6474

88 RTOG 0619: Post-op Adjuvant Phase II(R) in Planning, PI: David Raben Surgical Resection High Risk R A N D O M I Z E RT + DDP (30 mg/m 2, qw) RT + DDP (30 mg/m2, qw) + ZD6474 (300 mg daily)

89 Research Directions Topographic Targeting: IMRT - IGRT Tumor Control Toxicity Biologic Targeting: signaling pathway pattern of relapse Normal Tissue Protection: use of growth factors

90 Grade 4 Mucositis

91 KGF Palifermin (Kepivance ) FGF: Fibroblast growth factor. Finch PW, et al. Science 245:752, 1989 Farrell CL, et al. Cancer Res 58:933, 1998 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

92 Palifermin - biological activity in human buccal mucosa Pre-palifermin H&E H&E = hematoxylin and eosin 24 hr post-palifermin (40 µg/kg/day for 3 days) H&E

93 Incidence (%) Mean Duration (Days) Effect of Palifermin (rhukgf) on Mucositis Patients Undergoing TBI + CTH + AuBMT (Phase III) Grade 4 Mucositis p < % 20% Placebo Palifermin n = 106 n = p < (95% CI) 6.7d (5.3, 8.0) 3.7 Placebo (n = 106) Adapted from Spielberger R, NEJM 351: , 2004 Palifermin (n = 106)

94 Screening Randomization RTOG 0435: KGF in Reducing Mucositis Phase III Trial, PI: D. Rosenthal If ulcerative OM at week 7 Palifermin Placebo RT x 70Gy/7 weeks* CDDP 100 mg/m 2 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

95 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