Current Status Of Hypoxia And Radiotherapy PMH 50th 2008 PMH 50th - - PowerPoint PPT Presentation

Current Status Of Hypoxia And Radiotherapy

PMH 50th 2008 PMH 50th 2008

Tony Fyles MD, FRCPC y y Tumor Microenvironment Group Radiation Medicine Program Princess Margaret Hospital Princess Margaret Hospital University of Toronto

Oxygen Measurement using Eppendorf Oxygen using Eppendorf Oxygen electrode

Hypoxia and Clinical Outcome

Author Tumor Site Patients OS/DFS Local Cont Distant Metastases Fyles, 2002 Cervix 106 Yes

±

Yes Hockel, 1996 Cervix 89 Yes

±

Knocke, 1999 Cervix 51 Yes

±

Lyng, 2000 Cervix 40 Yes

±*

Brizel, 1999 H&N 63 Yes Yes Nordsmark, 1996 H&N 35 Yes Nordsmark, 2000 H&N 31 Yes Rudat, 2000 H&N 41 Yes Stadler, 1999 H&N 59 Yes B i l 1996 S 22 Y N Y Brizel, 1996 Sarcoma 22 Yes No Yes Nordsmark, 2001 Sarcoma 28 Yes No Yes

MARGINAL PROBABILITY

1.0

OF DISTANT RELAPSE

HP5 ≤50 0.8 HP5 ≤50 HP5 >50 robability 0.6 0 4 P value = 0.0028 P 0.4 0.2 1 2 3 4 5 Length of Follow-Up (years) 1 2 3 4 5

Clinical Implications of Tumour p Hypoxia

urs c Tumou f Hypoxic

Percent o

Negative Equivocal Positive

P

S Nodal Status

Pitson et al. (IJROBP 2001)

Hypoxia in Clinical Practice ypo a C ca act ce

1.0 1.0 0.8 0.8 val val

Pelvic Node Pelvic Node -

0.4 0.4 0.6 0.6 Disease Free Surviv Disease Free Surviv

Pelvic Node Pelvic Node - Pelvic node ? Pelvic node ?

0.2 0.2 D D

Pelvic node + Pelvic node +

1 1 2 2 3 3 4 4 5 5 0.0 0.0 Years to Relapse or Death Years to Relapse or Death

Oxygen measurements to select patient for Oxygen measurements to select patient for PA RT PA RT

Hypoxia in Clinical Practice Hypoxia in Clinical Practice

1.0 1.0 0.8 0.8 vival vival

Pelvic node ?, Oxic 1 Pelvic node ?, Oxic 10

0.4 0.4 0.6 0.6 Disease Free Surv Disease Free Surv

Pelvic node ?, Hypoxic 1 Pelvic node ?, Hypoxic 10 Pelvic Node Pelvic Node -

• 0.2

0.2

Pelvic node ?, Hypoxic 1 Pelvic node ?, Hypoxic 1 Pelvic node + Pelvic node +

O t t l t ti t O t t l t ti t

1 1 2 2 3 3 4 4 5 5 0.0 0.0 Years to Relapse or Death Years to Relapse or Death

Oxygen measurements to select patient Oxygen measurements to select patient for PA RT for PA RT

Hypoxia Is Not Related to Anemia

g)

• Hypoxia

Hypoxia vs

• vs. Hemoglobin In Cervix Cancer

. Hemoglobin In Cervix Cancer

<5 mmHg

• action (%
• poxic Fra
• 80

100 120 140 Hy

• 80

100 120 140 Initial Hemoglobin (g/L)

Fyles AW et al. Radiother Oncol. 2000;57:13-19.

Heterogeneous CA9 staining of STS

A B C D C D

CA 9 H and E

Summary

• Hypoxia is heterogeneous in tumours and is

i t d ith t t t t associated with poor treatment outcome

• Hypoxia is associated with metastatic disease

(including nodal disease)

• Hypoxia is associated with poor local control in

yp p head and neck cancer but not cervix cancer

• Anemia is not related to hypoxia

Anemia is not related to hypoxia

Tumor Interstitial Fluid Pressure Tumor Interstitial Fluid Pressure

↑ Capillary Capillary ↑ Capillary Capillary permeability permeability ↑ Interstitial Interstitial Distension of Distension of interstitial interstitial

↑ IFP IFP

Abnormal Abnormal lymphatics lymphatics fluid fluid interstitial interstitial matrix matrix

↑ IFP IFP

lymphatics lymphatics Fibroblast Fibroblast activation activation Contraction Contraction

• f interstitial
• f interstitial

collagen collagen ↑ Cytokines Cytokines (PDGF) (PDGF) collagen collagen

Long Term Performance of IFP and Hypoxia in Long-Term Performance of IFP and Hypoxia in Cervix Cancer – RT Alone

5 year DFS was 58% in patients with

• xygenated tumours and 42% for

patients with hypoxic tumours (p=0.05) 5 year DFS was 63% in patients with low IFP and 42% for patients with high IFP (p=0.001)

0.8 1.0 rvival 0.8 1.0 rvival 0.2 0.4 0.6 Disease-free sur HP5≤50 0.2 0.4 0.6 Disease-free sur IFP≤19 2 4 6 8 10 12 0.0 Time to relapse or death HP5≤50 HP5>50 2 4 6 8 10 12 0.0 Time to relapse or death IFP≤19 IFP>19

H i IFP H i IFP M lti i t A l i M lti i t A l i Hypoxia vs. IFP Hypoxia vs. IFP – Multivariate Analysis Multivariate Analysis

HP HP5 IFP IFP α Tumor size Tumor size α Tumor size Tumor size α LN’s LN’s Yes Yes Pelvic recurrence Pelvic recurrence Yes Yes Distant recurrence Distant recurrence Yes Yes Yes Yes

Hypoxia and IFP in Cervix Cancer: T t t ith RT CT Treatment with RT- CT

0.8 1.0 al

| | | || | | | | |||| |||||| | | | |

0.8 1.0 al

|| || | || || | || ||| || | | | | |

0.4 0.6 sease-free Surviva

| | | | | | | | || | || | | | | | | | | | | | | | | || || | | || | | || | | | || | | | | || | || | || ||| | || | | | | | | | || | | | | |

Continuous:HR=1.01, 95% CI:1-1.02, p-value=0.037 0.4 0.6 sease-free Surviva

| ||||| | | | | | | ||| |||| | ||| | | | | | | || || | | | || | || | | | | | | || | | | | | | | || | || | | | | || | | || | | | | |

Continuous:HR=0.99, 95% CI:0.97-1.02, p-value=0.66 2 4 6 8 0.0 0.2 Dis HP5<=57, n=81, 3y DFS=66% HP5>57, n=83, 3y DFS=53% HP5>57 vs. HP5<=57, HR=1.31, 95% CI:0.79-2.19, Log-rank p-value=0.31 2 4 6 8 0.0 0.2 Dis IFP<=17, n=80, 3y DFS=56% IFP>17, n=78, 3y DFS=58% IFP>17 vs. IFP<=17, HR=0.85, 95% CI:0.51-1.42, Log-rank p-value=0.53 2 4 6 8 Time to relapse or death (years) 2 4 6 8 Time to relapse or death (years)

Hypoxia marginally significant, IFP not significant yp g y g , g

Hypoxia in Cervix Cancer RT vs Chemo RT

HYPOXIC HP

RT vs Chemo-RT

0.8 1.0 al

|||| | || || |||| | | | | || | | |||| | || || |||| | | | | || | |

HYPOXIC group, HP5>50 RT, n=52, 3y DFS=42% RT+Cis, n=98, 3y DFS=57% RT+Cis vs. RT, HR=0.61, 95% CI:0.38-0.99, Log-rank p-value=0.045 0.8 1.0 al

| | | | | | | | |

0.6 se-free Surviva

| | | | || | | | || | | | | | ||| || || || |||| | || | | || || | | | || | | | | | | | | | | | || | | | || | | | | | ||| || || || |||| | || | | || || | | | || | | | | | | |

, , y % 0.6 se-free Surviva

| | | | | | | || || | | | || | | | | | | || | | | | | | | | | | | | | | | | | | | | | | | | || || | || | | ||

0.2 0.4 Diseas

| | | || | | | | | | | | | | | | | | | | | || | | | | | | | | | | | | | |

0.2 0.4 Diseas OXIC group, HP5<=50 RT+Cis vs. RT, HR=0.98, 95% CI:0.55-1.74, Log-rank p-value=0 93 2 4 6 8 10 12 14 0.0 2 4 6 8 10 12 14 0.0 RT, n=54, 3y DFS=66% RT+Cis, n=66, 3y DFS=63% Log rank p value=0.93 Time to relapse or death (years) Time to relapse or death (years)

IFP in Cervix Cancer RT vs Chemo RT

HIGH IFP IFP 1

RT vs Chemo-RT

0.8 1.0 al

| | | | | || ||| | | | || | |

0.8 1.0 al

|| ||| |||| | || | || ||| |||| | || |

HIGH IFP group, IFP>17.5 RT, n=57, 3y DFS=44% RT+Cis, n=73, 3y DFS=57% RT+Cis vs. RT, HR=0.62, 95% CI:0.37-1.02, Log-rank p-value=0.056 0.6 se-free Surviva

| | | | | | | | | | | | | | || | | | | || | | ||||| | | | | | ||| || || | ||| || | | | | | || || | | | || |

0.6 se-free Surviva

| | | | | | | | | | | | | || | | | | | | | || | | | | | | || | | || | | | | | | | | | | | | | | | | | || | | | | | | | || | | | | | | || | | || | | | |

, , y % 0.2 0.4 Diseas

|

LOW IFP group, IFP<=17.5 RT+Cis vs. RT, HR=1.5, 95% CI:0.82-2.76, Log-rank p-value=0 19 0.2 0.4 Diseas

| | | | | | | | || | | | | | | | | | | | | | | | | || | | | | | | | |

2 4 6 8 10 12 14 0.0 RT, n=45, 3y DFS=71% RT+Cis, n=85, 3y DFS=57% Log rank p value=0.19 2 4 6 8 10 12 14 0.0 Time to relapse or death (years) Time to relapse or death (years)

Hypoxia and High IFP Predict for Chemo Hypoxia and High IFP Predict for Chemo-

• RT

RT Response in Cervix Cancer Response in Cervix Cancer Response in Cervix Cancer Response in Cervix Cancer

1.0

| | ||

HIGH IFP group, IFP>17.5 RT+Cis vs. RT, HR=0.62, 95% CI:0.37-1.02, Log-rank p-value=0.056 1.0

| |

HIGH HP5 group, HP5>50 RT+Cis vs. RT, HR=0.61, 95% CI:0.38-0.99, Log-rank p-value=0.045 0 6 0.8 vival

| | | | | | | | | | || | | | || | | ||||| | | | || | | || ||| | || | | | | || | | | ||| | ||| | | | | | | | ||

RT, n=57, 3y DFS=44% RT+Cis, n=73, 3y DFS=57% g 0 6 0.8 vival

| | || | | | | | | | | | | | | | | | || | | | ||| | | | | || |||| | | | | | | | ||| | | | | || | ||| | | || || ||| | | ||| ||

RT, n=52, 3y DFS=42% RT+Cis, n=98, 3y DFS=57% g 0.4 0.6 Disease-free Surv

| | | | | | | || | || | | | |||| | | | || || || | | | | | | | | | | | | | | | | || || | | | | | | | | || || | || | | || | | | || | || | | || | | | |

0.4 0.6 Disease-free Surv

| | | || || | | ||| | | | | | | | | | | | | || |||| | | | | | | | | | | | || | | | | | | | | | | | || || | | | | | | || ||| || || || | | | || || | | | | | | |

0.2

|

LOW IFP group, IFP<=17.5 RT n=45 3y DFS=71% RT+Cis vs. RT, HR=1.5, 95% CI:0.82-2.76, Log-rank p-value=0.19 0.2 LOW HP5 group, HP5<=50 RT n=54 3y DFS=66% RT+Cis vs. RT, HR=0.98, 95% CI:0.55-1.74, Log-rank p-value=0.93

|

2 4 6 8 10 12 14 0.0 Time to relapse or death (years) RT, n=45, 3y DFS=71% RT+Cis, n=85, 3y DFS=57% 2 4 6 8 10 12 14 0.0 Time to relapse or death (years) RT, n=54, 3y DFS=66% RT+Cis, n=66, 3y DFS=63%

IFP in Cervix Cancer Multivariate Analysis: DFS Multivariate Analysis: DFS

Low IFP HR p

Size 1.38 0.0002 Equivocal LN’s 2.22 0.029 Positive LN’s 1 74 0 12

Low IFP HR p

Positive LN’s 1.74 0.12 RT vs. RTCT 0.81 0.51 Size 1.27 0.0024

High IFP HR p

Equivocal LN’s 1.4 0.33 Positive LN’s 2.13 0.035 RT vs. RTCT 2.01 0.025

Summary Hypoxia and IFP Interaction with Cisplatin

• Prognostic effect of IFP and hypoxia was diminished
• Prognostic effect of IFP and hypoxia was diminished

with addition of chemo to RT

• This appears to be due to a differential effect of

chemo

• CT marginally improved DFS compared to RT alone

in hypoxic tumors, independent of clinical prognostic in hypoxic tumors, independent of clinical prognostic factors

• CT significantly improved DFS compared to RT alone

in high IFP tumors independent of clinical prognostic in high IFP tumors, independent of clinical prognostic factors

Possible Mechanisms: Hypoxia and IFP Interaction with Cisplatin Hypoxia and IFP Interaction with Cisplatin

Hypoxia

• Hypoxia sensitizes cells to cisplatin by ↓ DNA

repair

• Hypoxic tumors are more likely to have occult
• Hypoxic tumors are more likely to have occult

metastatic (nodal) disease and greater

• pportunity to benefit from cisplatin

IFP

• Inconsistent with drug delivery effect
• Rapidly proliferating tumors have high IFP and are
• Rapidly proliferating tumors have high IFP and are

more sensitive to cisplatin

• High IFP influences cisplatin biodistribution or

t b li metabolism

Conclusions Conclusions

• IFP and hypoxia are independent predictors of

IFP and hypoxia are independent predictors of survival in cervix cancer survival in cervix cancer survival in cervix cancer survival in cervix cancer

• High IFP is associated with both local and distant

High IFP is associated with both local and distant recurrence recurrence

• IFP and hypoxia may be biomarkers of chemo

IFP and hypoxia may be biomarkers of chemo-

• RT

RT response response

• IFP is also a marker of angiogenesis, a promising

IFP is also a marker of angiogenesis, a promising therapeutic target in cancer therapeutic target in cancer

• IFP may be a useful marker of biologic response to

IFP may be a useful marker of biologic response to anti anti-

• angiogenic treatment.

angiogenic treatment.

Hypoxic Biomarkers in Clinical Development

Extrinsic

• Hypoxia Probes
• Hypoxia Probes
• Pimonidazole, EF5

Intrinsic

• CA IX, HIF, osteopontin

Hypoxia Imaging

• PET
• DCE-MR and CT

Triple overlay HIF CA IX and EF5 Triple overlay HIF, CA IX and EF5

DFS curves for CA-IX or HP5 (Toronto) CA-IX and Cervix Ca outcome – DFS, mets and local control (Manchester)

1 0 rvival 0 6 0.8 1.0 Disease-free sur 0.2 0.4 0.6 Log rank p-value = 0.022 HP5 50 46 Years to first failure 1 2 3 4 5 6 0.0 HP5<=50 , n= 46 HP5>50 , n= 48

Locoregional Control and Overall Survival According to the Locoregional Control and Overall Survival According to the Combined Status of HIF- 2 and CA9

Cervix Hypoxia Collaboration Cervix Hypoxia Collaboration

Goal t d l l f D t b d t

• to develop a panel of

hypoxia-associated markers

• Databases and tumour

banks form Calgary (n=150), Vancouver

• to validate hypothesis

that chemo-RT is of benefit only in hypoxic ( ) (n=50) and PMH (n=150)

• TMA’s to be analyzed in

Calgary using HistoRx benefit only in hypoxic tumours Calgary using HistoRx (Tony Magliocco)

Phase I/II Study of Sorafenib in Patients With Cervix Ca Phase I/II Study of Sorafenib in Patients With Cervix Ca

Phase I: Sorafenib

n=3-6 DL 100 mg bid 1 n 3 6 n=3-6 DL - DL 1 200 mg bid 1

Phase II: Sorafenib 400 mg bid

30 n=3-6 DL 2 400 mg bid

External RT + Cisplatin 40 mg/m

2

n=30

• 2
• 1

2 1 5 4 3 Time (weeks) ( ) Biomarkers at weeks –2, 0, 2 (pO2 , IFP, fCT, dMRI , MVD, VEGF,…) ,

Response to Sorafenib: DCE MR Response to Sorafenib: DCE MR

Patient 1 Patient 1 Cervix T2b N0 Patient 2 C i Cervix T1b N1 Baseline Day 7 of Sorafenib Day 21, S+RT

Clinical Implications

• Drugs targeted at IFP/angiogenesis and

h i ill lik l b ff ti l i l t d hypoxia will likely be effective only in selected patients Bi k i i

• Biomarker assays or imaging are necessary

to optimize use of such agents

• Best markers still to be established

Biomarker Conclusions

• Multiple hypoxic markers are prognostic in patients

with head and neck and cervix cancer with head and neck and cervix cancer

• Osteopontin and FMISO PET are predictive of

response to hypoxic sensitizers/cytotoxins p yp y

• TPZ has promise and is undergoing evaluation in

Phase III RCT

• Biologically-targeted agents are in Phase I/II trials in

combination with radiation and chemotherapy

Hypoxia in Prostate Cancer Hypoxia in Prostate Cancer

N Risk Risk Group Group Method Method % Hypoxic % Hypoxic Median pO Median pO2 (mm Hg) (mm Hg)

PMH PMH 237 237 Inter Inter pO pO2 35% 35% 6.7 6.7 Boddy Boddy HIF1 HIF1α, Boddy Boddy (2005) (2005) 149 149 pT1 pT1-

• 3

3 HIF1 HIF1α, VEGF VEGF 80% 80% Movsas Movsas T1 T1 3 O 2 4 2 4

• sas
• sas

(2002) (2002) 55 55 cT1 cT1-3 pO pO2 2.4 2.4 Carnell Carnell 43 43 cT1 cT1 3 Pimo Pimo 92% 92% (2006) (2006) 43 43 cT1 cT1-3 Pimo Pimo 92% 92% Morton Morton 17 17 High High pO pO2 67% 67% 2.5 2.5

2

Hypoxia Confers Poor Outcome? Hypoxia Confers Poor Outcome?

1.0

Oxic, n=72 e free

0 6 0.8

Hypoxic, n=71 A-failure

0.4 0.6

Early PMH Experience

yp , PS

0.2

Log-rank p = 0.018 (Median follow-up 20 months)

0.0 0.5 1.0 1.5 2.0 2.5 3.0 0.0

Years from RT completion

Androgen Withdrawal (Bicalutamide) Androgen Withdrawal (Bicalutamide) Reduces Hypoxia in Patients Reduces Hypoxia in Patients

50 60

g)

50 60

g)

40 50

O2 (mm Hg

Significant reduction in hypoxia for all patients (p<0 005)

pO2 40 50

O2 (mm Hg

Significant reduction in hypoxia for all patients (p<0 005)

pO2 20 30

atment pO

(p<0.005)

20 30

atment pO

(p<0.005)

10 20

Post-Trea

Reduced hypoxia (p<0.001) No change Increased hypoxia (p<0.001) 10 20

Post-Trea

Reduced hypoxia (p<0.001) No change Increased hypoxia (p<0.001) Reduced hypoxia (p<0.001) No change Increased hypoxia (p<0.001) 10 20 30 40 50 60

Pre-Treatment pO 2 (mm Hg) P

(Mean ± se) 10 20 30 40 50 60

Pre-Treatment pO 2 (mm Hg) P

(Mean ± se) (Mean ± se)

Pre-Treatment pO 2 (mm Hg) Pre-Treatment pO 2 (mm Hg)

Milosevic Cancer Res. 2007 Jul 1;67(13):6022-5

Multidisciplinary Strategy Strategy

4D Imaging Biologic Imaging

F S

0.6 0.8 1.0 Oxic, low IFP O i hi h IFP Hypoxic, low IFP

F S

0.6 0.8 1.0 Oxic, low IFP O i hi h IFP Hypoxic, low IFP

D F

0.0 0.2 0.4 Log-rank p = 0.0097 Hypoxic, high IFP Oxic, high IFP

D F

0.0 0.2 0.4 Log-rank p = 0.0097 Hypoxic, high IFP Oxic, high IFP

50 60 70

mmHg) Time (y) 1 2 3 4 5 Time (y) 1 2 3 4 5

10 20 30 40

re-treatment IFP (m

ZD6126 treated Control Trendline (ZD6126)

Cervix Cancer

10 20 30 40 50 60

Post-treatment IFP (mmHg) Pr

( ) Line of Identity (Control)

Lab IMRT

Acknowledgements g

Clinic Clinic Biostatistics Biostatistics Lab Lab

Ri h d Hill Ri h d Hill Mike Milosevic Mike Milosevic Amit Oza Amit Oza Masoom Haider Masoom Haider Melania Pintilie Melania Pintilie Shirley Brown Shirley Brown Richard Hill Richard Hill David Hedley David Hedley Rob Bristow Rob Bristow I Y I Y Masoom Haider Masoom Haider Lee Manchul Lee Manchul Wilfred Levin Wilfred Levin Fernanda Herrera Fernanda Herrera Clinical Support Clinical Support Ivan Yeung Ivan Yeung M-

• C Kavanagh

C Kavanagh Trudey Nicklee Trudey Nicklee Fernanda Herrera Fernanda Herrera Philip Chan Philip Chan Rob Dinniwell Rob Dinniwell Barbara Bachtiary Barbara Bachtiary Ami Syed Ami Syed Judy Quintos Judy Quintos Barbara Bachtiary Barbara Bachtiary Karen Lim Karen Lim Supported by the National Cancer Institute f C d ith f d f th T F R

• f Canada with funds from the Terry Fox Run