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 Tumor Distant Author Patients OS/DFS Local Cont Site 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 Brizel, 1996 l 1996 Sarcoma S 22 22 Y Yes N No Y Yes Nordsmark, 2001 Sarcoma 28 Yes No Yes
MARGINAL PROBABILITY OF DISTANT RELAPSE 1.0 HP5 ≤ 50 HP5 ≤ 50 HP5 >50 0.8 robability 0.6 P value = 0.0028 0 4 0.4 P 0.2 0 0 0 1 1 2 2 3 3 4 4 5 5 Length of Follow-Up (years)
Clinical Implications of Tumour p Hypoxia urs c Tumou f Hypoxic Percent o P Negative Equivocal Positive Nodal Status S 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 - Pelvic Node Pelvic Node - Disease Free Surviv Disease Free Surviv 0.6 0.6 Pelvic node ? Pelvic node ? 0.4 0.4 D D Pelvic node + Pelvic node + 0.2 0.2 0.0 0.0 0 1 2 3 4 5 0 1 2 3 4 5 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 Pelvic node ?, Oxic 1 Pelvic node ?, Oxic 1 0 vival vival Disease Free Surv Disease Free Surv 0.6 0.6 Pelvic Node Pelvic Node - - 0.4 0.4 Pelvic node ?, Hypoxic 1 Pelvic node ?, Hypoxic 1 Pelvic node ?, Hypoxic 1 Pelvic node ?, Hypoxic 1 0 0.2 0.2 Pelvic node + Pelvic node + 0.0 0.0 0 0 1 1 2 2 3 3 4 4 5 5 Years to Relapse or Death Years to Relapse or Death O Oxygen measurements to select patient Oxygen measurements to select patient O t t t t l l t t ti ti t t for PA RT for PA RT
Hypoxia Is Not Related to Anemia Hypoxia Hypoxia vs vs . Hemoglobin In Cervix Cancer . Hemoglobin In Cervix Cancer � g) <5 mmHg � � � � � � � � � � � � � � � � � � � � � � � action (% � �� � � � � � � � � � � � � � � � � � � � � � � � � � � poxic Fra � � � � � � � � � � � � � � � � � � � � � � � � � � � � Hy � � � � 80 80 100 100 120 120 140 140 Initial Hemoglobin (g/L) Fyles AW et al. Radiother Oncol . 2000;57:13-19.
B D D Heterogeneous CA9 staining of STS H and E A C C CA 9
Summary • Hypoxia is heterogeneous in tumours and is associated with poor treatment outcome i t d ith t t t t • 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 Distension of Distension of ↑ Interstitial Interstitial ↑ IFP ↑ IFP IFP IFP interstitial interstitial interstitial interstitial fluid fluid matrix matrix Abnormal Abnormal lymphatics lymphatics lymphatics lymphatics Contraction Contraction ↑ Cytokines Cytokines Fibroblast Fibroblast of interstitial of interstitial (PDGF) (PDGF) activation activation collagen collagen 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 5 year DFS was 63% in patients with low oxygenated tumours and 42% for IFP and 42% for patients with high IFP patients with hypoxic tumours (p=0.05) (p=0.001) 1.0 1.0 rvival rvival 0.8 0.8 Disease-free sur Disease-free sur 0.6 0.6 0.4 0.4 0.2 0.2 HP5 ≤ 50 HP5 ≤ 50 IFP ≤ 19 IFP ≤ 19 HP5>50 IFP>19 0.0 0.0 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Time to relapse or death Time to relapse or death
H Hypoxia vs. IFP – Multivariate Analysis H Hypoxia vs. IFP i i IFP IFP M lti M lti Multivariate Analysis i t A i t A l l i i HP HP 5 IFP IFP α Tumor size α Tumor size 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 Treatment with RT- CT t t ith RT CT 1.0 1.0 | | | || | | | || ||| || || | |||| |||||| || || | | | || 0.8 0.8 | | | | | | al al | | | | | || sease-free Surviva sease-free Surviva | | | | | | | || | | | | | | | | || | ||||| | | || | | | | | | | | | | | | | | | | | | ||| 0.6 || 0.6 || | | | | || || | | || | | || | |||| | | | | | | | || | || | | | | || | | || | | | | | | | ||| | | | | || || | ||| | || | | | | | | | || | | | | | | | || || | | | || 0.4 0.4 Continuous:HR=1.01, 95% CI:1-1.02, p-value=0.037 Continuous:HR=0.99, 95% CI:0.97-1.02, p-value=0.66 Dis Dis HP5>57 vs. HP5<=57, HR=1.31, 95% CI:0.79-2.19, IFP>17 vs. IFP<=17, HR=0.85, 95% CI:0.51-1.42, Log-rank p-value=0.31 Log-rank p-value=0.53 0.2 0.2 HP5<=57, n=81, 3y DFS=66% IFP<=17, n=80, 3y DFS=56% HP5>57, n=83, 3y DFS=53% IFP>17, n=78, 3y DFS=58% 0.0 0.0 0 0 2 2 4 4 6 6 8 8 0 0 2 2 4 4 6 6 8 8 Time to relapse or death (years) 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 RT vs Chemo RT HYPOXIC group, HP5>50 HYPOXIC HP 0 1.0 1.0 RT+Cis vs. RT, HR=0.61, 95% CI:0.38-0.99, Log-rank p-value=0.045 | | |||| |||| | | || || || || |||| |||| | | | | | | 0.8 0.8 RT, n=52, 3y DFS=42% | | | | | | | RT+Cis, n=98, 3y DFS=57% , , y % al al || || || || | | | | | se-free Surviva se-free Surviva | | | | | | | | | | | | | | | | | | | | | | | | ||| || ||| || | | | | | | | | | 0.6 0.6 | | | || || | || | | || || || | | || |||| | || |||| | || || | | || | | || || || | || || | | | || | | | || | | | || | | | | | | | | | | | | | | | | | | | | | | || | | | | | | | | | | | | | | | || || || || | | | | | | | | | | | | 0.4 0.4 Diseas Diseas | | | | | | | | | | | | | | | | | | | | OXIC group, HP5<=50 0.2 0.2 | | RT+Cis vs. RT, HR=0.98, 95% CI:0.55-1.74, Log-rank p-value=0 93 Log rank p value=0.93 RT, n=54, 3y DFS=66% 0.0 0.0 RT+Cis, n=66, 3y DFS=63% 0 0 2 2 4 4 6 6 8 8 10 10 12 12 14 14 Time to relapse or death (years) Time to relapse or death (years)
IFP in Cervix Cancer RT vs Chemo-RT RT vs Chemo RT HIGH IFP group, IFP>17.5 HIGH IFP IFP 1 1.0 1.0 RT+Cis vs. RT, HR=0.62, 95% CI:0.37-1.02, Log-rank p-value=0.056 || || ||| ||| |||| |||| || ||| | | | | || 0.8 0.8 RT, n=57, 3y DFS=44% | | | RT+Cis, n=73, 3y DFS=57% , , y % || || | | al al | | | | | | | | | | se-free Surviva se-free Surviva | | | | | | | | ||||| | | | | | | | | | | | | | | || | ||| | | | | | | 0.6 0.6 | | || || || || | ||| || | | | | | | | | | | | | | | | | | || || | | | | | | | | | | | || | || | | | | || | || | | | | | | | | | | | || | | | || || | | | || | | | | | | | | | | | | | | | 0.4 0.4 Diseas Diseas | | | | | | | | | | | | || || | | | | | | | | | | | | | | | | | LOW IFP group, IFP<=17.5 0.2 0.2 RT+Cis vs. RT, HR=1.5, 95% CI:0.82-2.76, Log-rank p-value=0 19 Log rank p value=0.19 RT, n=45, 3y DFS=71% 0.0 0.0 RT+Cis, n=85, 3y DFS=57% 0 0 2 2 4 4 6 6 8 8 10 10 12 12 14 14 Time to relapse or death (years) Time to relapse or death (years)
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