current status of hypoxia and radiotherapy - imedex slides/1120 fyles - final... · current status...

Current Status Of Hypoxia And RadiotherapyPMH 50th 2008PMH 50th 2008

Tony Fyles MD, FRCPCy yTumor Microenvironment Group

Radiation Medicine ProgramPrincess Margaret HospitalPrincess Margaret Hospital

University of Toronto

Oxygen Measurement using Eppendorf Oxygenusing Eppendorf Oxygen

electrode

Hypoxia and Clinical OutcomeAuthor 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

Nord smark, 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 YBrizel, 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 ≤50HP5 >50

roba

bilit

y

0.6

0 4

P value = 0.0028

P 0.4

0.2

0 1 2 3 4 5

0

0

Length of Follow-Up (years)

1 2 3 4 5

Clinical Implications of Tumour pHypoxia

urs

c Tu

mou

f Hyp

oxic

Perc

ento

Negative Equivocal Positive

P

SNodal Status

Pitson et al. (IJROBP 2001)

Hypoxia in Clinical Practiceypo a C ca act ce

1.01.0

0.80.8

val

val

Pelvic NodePelvic Node --

0.40.4

0.60.6

Dis

ease

Fre

e Su

rviv

Dis

ease

Fre

e Su

rviv Pelvic Node Pelvic Node --

Pelvic node ?Pelvic node ?

0.20.2

DD

Pelvic node +Pelvic node +

00 11 22 33 44 55

0.00.0

Years to Relapse or DeathYears to Relapse or Death

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

Hypoxia in Clinical PracticeHypoxia in Clinical Practice

1.01.0

0.80.8

viva

lvi

val

Pelvic node ?, Oxic 1Pelvic node ?, Oxic 100

0.40.4

0.60.6

Dis

ease

Fre

e Su

rvD

isea

se F

ree

Surv

Pelvic node ?, Hypoxic 1Pelvic node ?, Hypoxic 100

Pelvic Node Pelvic Node --

0.20.2

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

Pelvic node +Pelvic node +

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

00 11 22 33 44 55

0.00.0

Years to Relapse or DeathYears to Relapse or Death

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

Hypoxia Is Not Related to Anemia

g)Hypoxia Hypoxia vsvs. Hemoglobin In Cervix Cancer. Hemoglobin In Cervix Cancer

<5 m

mH

gac

tion

(%

poxi

c Fr

a

80 100 120 140

Hy

80 100 120 140Initial Hemoglobin (g/L)

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

Heterogeneous CA9 staining of STS

A B

C DC D

CA 9 H and E

Summary

• Hypoxia is heterogeneous in tumours and is i t d ith t t t tassociated with poor treatment outcome

• Hypoxia is associated with metastatic disease (including nodal disease)

• Hypoxia is associated with poor local control in yp phead and neck cancer but not cervix cancer

• Anemia is not related to hypoxiaAnemia is not related to hypoxia

Tumor Interstitial Fluid PressureTumor Interstitial Fluid Pressure

↑↑ CapillaryCapillary↑↑ CapillaryCapillarypermeabilitypermeability

↑↑ InterstitialInterstitial Distension ofDistension ofinterstitialinterstitial ↑↑ IFPIFP

AbnormalAbnormallymphaticslymphatics

fluidfluid interstitialinterstitialmatrixmatrix

↑↑ IFPIFP

lymphaticslymphatics

FibroblastFibroblastactivationactivation

ContractionContractionof interstitialof interstitial

collagencollagen

↑↑ CytokinesCytokines(PDGF)(PDGF) collagencollagen

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

5 year DFS was 58% in patients with oxygenated 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

rviv

al 0.8

1.0

rviv

al0.2

0.4

0.6

Dis

ease

-free

sur

HP5≤500.2

0.4

0.6

Dis

ease

-free

sur

IFP≤19

0 2 4 6 8 10 12

0.0

Time to relapse or death

HP5≤50HP5>50

0 2 4 6 8 10 12

0.0

Time to relapse or death

IFP≤19IFP>19

H i IFPH i IFP M lti i t A l iM lti i t A l iHypoxia vs. IFP Hypoxia vs. IFP –– Multivariate AnalysisMultivariate Analysis

HPHP55 IFPIFP

αα Tumor sizeTumor sizeαα Tumor sizeTumor size

αα LN’sLN’s YesYes

Pelvic recurrencePelvic recurrence YesYes

Distant recurrenceDistant recurrence YesYes YesYes

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

0.8

1.0

al

| ||||| | |

|

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

| |0.8

1.0

al

|| || ||| | ||

||| |||||| |

| |

0.4

0.6

seas

e-fre

e Su

rviv

a | || || ||| || | | ||| | | | || | | | | ||| | | || | | | | | || | | |||

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

Continuous:HR=1.01, 95% CI:1-1.02, p-value=0.0370.4

0.6

seas

e-fre

e Su

rviv

a

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

| ||| || | | | ||

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

Continuous:HR=0.99, 95% CI:0.97-1.02, p-value=0.66

0 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

0 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

0 2 4 6 8

Time to relapse or death (years)

0 2 4 6 8


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

Hypoxia in Cervix CancerRT vs Chemo RT

HYPOXIC HP 0

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-fr

ee S

urvi

va

|

|| | || || |

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

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

|| | || || |

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

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

, , y %

0.6

se-fr

ee S

urvi

va

| || |

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

| | ||| | || | | |

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

0.2

0.4

Dis

eas || | || || |

| | | | | | || | |

|

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

|0.2

0.4

Dis

eas

OXIC group, HP5<=50RT+Cis vs. RT, HR=0.98, 95% CI:0.55-1.74,Log-rank p-value=0 93

0 2 4 6 8 10 12 14

0.0

0 2 4 6 8 10 12 14

0.0RT, 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 CancerRT 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



0.6

se-fr

ee S

urvi

va

|| | |

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

| | || |

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

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

0.6

se-fr

ee S

urvi

va

|

| | | | |

|| | || | |||

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

| | | | |

|| | || | |||

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

, , y %

0.2

0.4

Dis

eas

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

0.2

0.4

Dis

eas | |

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

| || | |

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

0 2 4 6 8 10 12 14

0.0RT, n=45, 3y DFS=71%RT+Cis, n=85, 3y DFS=57%

Log rank p value=0.19

0 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 ChemoHypoxia and High IFP Predict for Chemo--RT RT Response in Cervix CancerResponse in Cervix CancerResponse in Cervix CancerResponse in Cervix Cancer

1.0

||||

HIGH IFP group, IFP>17.5


1.0

||

HIGH HP5 group, HP5>50


0 6

0.8

viva

l

|

|| | |

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

| |

|| |||||| |||

||||||

|| ||||||| |

|||||||||

||||

||

|||||


g

0 6

0.8

viva

l

|

| |||

||||

|

|

| ||||||

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

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

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

| | ||||||

| |

|||

||


g

0.4

0.6

Dis

ease

-free

Sur

v | |

| | || |

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

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

|

| | || |

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

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

0.4

0.6

Dis

ease

-free

Sur

v

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

| | |

|| | || | | |

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

|

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

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

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

0.2

|LOW IFP group, IFP<=17.5

RT n=45 3y DFS=71%


0.2

LOW HP5 group, HP5<=50

RT n=54 3y DFS=66%


|

0 2 4 6 8 10 12 14

0.0



0 2 4 6 8 10 12 14

0.0



IFP in Cervix CancerMultivariate Analysis: DFSMultivariate Analysis: DFS

Low IFP HR pSize 1.38 0.0002Equivocal LN’s 2.22 0.029Positive LN’s 1 74 0 12

Low IFP HR p

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

Size 1.27 0.0024High IFP HR p

Equivocal LN’s 1.4 0.33Positive LN’s 2.13 0.035RT 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 prognosticin hypoxic tumors, independent of clinical prognostic factors

• CT significantly improved DFS compared to RT alone in high IFP tumors independent of clinical prognosticin high IFP tumors, independent of clinical prognostic factors

Possible Mechanisms: Hypoxia and IFP Interaction with CisplatinHypoxia 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 opportunity 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 limetabolism

ConclusionsConclusions•• IFP and hypoxia are independent predictors of IFP and hypoxia are independent predictors of

survival in cervix cancersurvival in cervix cancersurvival in cervix cancersurvival in cervix cancer

•• High IFP is associated with both local and distant High IFP is associated with both local and distant recurrencerecurrence

•• IFP and hypoxia may be biomarkers of chemoIFP and hypoxia may be biomarkers of chemo--RT RT responseresponse

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

•• IFP may be a useful marker of biologic response to IFP may be a useful marker of biologic response to antianti--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 EF5Triple 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

rviv

al

0 6

0.8

1.0

Dis

ease

-free

sur

0.2

0.4

0.6

Log rank p-value = 0.022

HP5 50 46

Years to first failure

0 1 2 3 4 5 6

0.0

HP5<=50 , n= 46HP5>50 , n= 48

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

Cervix Hypoxia CollaborationCervix Hypoxia CollaborationGoal

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 HistoRxbenefit only in hypoxic

tumours Calgary using HistoRx (Tony Magliocco)

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

Phase I: Sorafenib

n=3-6DL100 mg bid

1 n 3 6

n=3-6

DL -

DL 1200 mg bid

1

Phase II: Sorafenib 400 mg bid30

n=3-6DL 2400 mg bid

External RT + Cisplatin 40 mg/m2

n=30

-2 -1 0 21 543Time (weeks)( )

Biomarkers at weeks –2, 0, 2(pO2 , IFP, fCT, dMRI , MVD, VEGF,…),

Response to Sorafenib: DCE MRResponse to Sorafenib: DCE MR

Patient 1Patient 1CervixT2b N0

Patient 2C iCervixT1b 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 dhypoxia 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 cancerwith head and neck and cervix cancer

• Osteopontin and FMISO PET are predictive of response to hypoxic sensitizers/cytotoxinsp 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 CancerHypoxia in Prostate Cancer

NNRiskRisk

GroupGroupMethodMethod % Hypoxic % Hypoxic

Median pOMedian pO22

(mm Hg)(mm Hg)

PMHPMH 237237 InterInter pOpO22 35%35% 6.76.7

BoddyBoddy HIF1HIF1αα,,BoddyBoddy(2005)(2005)

149149 pT1pT1--33HIF1HIF1αα,,VEGFVEGF

80%80%

MovsasMovsasT1T1 33 OO 2 42 4

o saso sas(2002)(2002)

5555 cT1cT1--33 pOpO22 2.42.4

CarnellCarnell4343 cT1cT1 33 PimoPimo 92%92%

(2006)(2006)4343 cT1cT1--33 PimoPimo 92%92%

MortonMorton 1717 HighHigh pOpO22 67%67% 2.52.522

Hypoxia Confers Poor Outcome?Hypoxia Confers Poor Outcome?

1.0 Oxic, n=72e

free

0 6

0.8

Hypoxic, n=71

A-fa

ilure

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

60g) 50

60g)

40

50

O2(m

m H

g

Significant reduction inhypoxia for all patients

(p<0 005)pO240

50

O2(m

m H

g

Significant reduction inhypoxia for all patients

(p<0 005)pO2

20

30

atm

ent p

O (p<0.005)

20

30

atm

ent p

O (p<0.005)

10

20

Post

-Tre

a

Reduced hypoxia (p<0.001)No changeIncreased hypoxia (p<0.001)10

20

Post

-Tre

a

Reduced hypoxia (p<0.001)No changeIncreased hypoxia (p<0.001)

Reduced hypoxia (p<0.001)No changeIncreased hypoxia (p<0.001)

00 10 20 30 40 50 60

Pre-Treatment pO 2 (mm Hg)

P (Mean ± se)0

0 10 20 30 40 50 60Pre-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

MultidisciplinaryStrategyStrategy

4DImaging

BiologicImaging

FS

0.6

0.8

1.0Oxic, low IFP

O i hi h IFP

Hypoxic, low IFP

FS

0.6

0.8

1.0Oxic, low IFP

O i hi h IFP

Hypoxic, low IFP

DF

0.0

0.2

0.4

Log-rank p = 0.0097

Hypoxic, high IFP

Oxic, high IFPDF

0.0

0.2

0.4

Log-rank p = 0.0097

Hypoxic, high IFP

Oxic, high IFP

50

60

70

mm

Hg)

Time (y)0 1 2 3 4 5

Time (y)0 1 2 3 4 5

10

20

30

40

re-tr

eatm

ent I

FP (m

ZD6126 treated

Control

Trendline (ZD6126)

Cervix Cancer

0

0 10 20 30 40 50 60

Post-treatment IFP (mmHg)

Pr

( )

Line of Identity (Control)

Lab IMRT

Acknowledgementsg

ClinicClinic BiostatisticsBiostatistics LabLabRi h d HillRi h d HillMike MilosevicMike Milosevic

Amit OzaAmit OzaMasoom HaiderMasoom Haider

Melania PintilieMelania PintilieShirley BrownShirley Brown

Richard HillRichard HillDavid HedleyDavid HedleyRob BristowRob BristowI YI YMasoom HaiderMasoom Haider

Lee ManchulLee ManchulWilfred LevinWilfred LevinFernanda HerreraFernanda Herrera

Clinical SupportClinical Support

Ivan YeungIvan YeungMM--C KavanaghC KavanaghTrudey NickleeTrudey NickleeFernanda HerreraFernanda Herrera

Philip ChanPhilip ChanRob DinniwellRob DinniwellBarbara BachtiaryBarbara Bachtiary

Ami SyedAmi SyedJudy QuintosJudy Quintos

Barbara BachtiaryBarbara BachtiaryKaren LimKaren Lim

Supported by the National Cancer Institute f C d ith f d f th T F Rof Canada with funds from the Terry Fox Run

current status of hypoxia and radiotherapy - imedex slides/1120 fyles - final... · current status...

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