Download Oxygen and Cancer: friend or foe?

Oxygen and Cancer: friend or foe?
Part 1: Scientific part
Dirk de Ruysscher
Part 2: Organisational part
Harald Moonen
Cancer
=
Genetic disease
with 6 features
The 6 Hallmarks of Cancer
HYPOXIA
=
LACK OF OXYGEN
Tumor hypoxia
Hypoxia
Hypoxia
1 mm size
Tumor hypoxia
Abnormal vasculature is a prime cause of hypoxia in cancer
Colon xenograft
Normal colon
Corrosion
castings
Two types of hypoxia
blood vessel
oxygen
glucose
conc
Distance from vessel
Heterogeneity in Oxygenation
a)
b)
c)
d)
Amount (%) amongst patients
In severity
In space
In time
Hypoxia tolerance/angiogenesis
Hypoxia tolerance varies amongst tumors
blood vessel
oxygen
glucose
conc
Distance from vessel
Tumour hypoxia,
does it exist in human tumours?
pO2 measurements indicate most tumors are hypoxic
20
Normal tissue
Relative frequency (%)
Relative frequency (%)
Nordsmark et al. Acta Oncol 1994
15
10
5
0
0
20
40
60
80
Oxygen partial pressure (mmHg)
20
Tumour
15
10
5
0
0
20
40
60
80
Median Oxygen Levels of Human Tumors
Tumor Type
Median pO2
(mmHg)
Reference
Glioblastoma
5.6 (14 pts)
Collingridge et al, 1999
Head & Neck
7.4 (41 pts)
4.6 (63 pts)
Rudat et al, 2000
Brizel et al, 1999
Lung
12.8 (26 pts)
Le & Stevens (pers. comm.)
Breast
10.0 (15 pts)
Vaupel et al, 2002
2.7 (7 pts)
Koong et al, 2000
10.0 (51 pts)
5.0 (74 pts)
Knocke et al, 1999
Fyles et al, 1998
Prostate
2.4 (59 pts)
4.5 (55 pts)
Movsas et al, 2001
Parker et al, 2004
Soft Tissue Sarcoma
6.2 (34 pts)
Brizel et al, 1996
Pancreas
Cervix
Cf. normal = 30-60 mmHg
(A)
Baseline [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) of patient with
T2N2b squamous cell carcinoma of the pyriform fossa with left nodal mass
(A)
Baseline [18F]-fluorodeoxyglucose
(FDG) positron emission
tomography (PET) of patient with
T2N2b squamous cell carcinoma of
the pyriform fossa with left nodal
mass.
(B)
(B) [18F]-fluoromisonidazole
(FMISO) -PET at baseline,
nonhypoxic primary tumor, and
hypoxic node.
(C)
C) FDG-PET 12 weeks after
chemoboost, complete response in
nonhypoxic primary tumor, and
poor response in hypoxic node.
Residual tumor in nodal mass was
confirmed pathologically after neck
dissection.
Rischin, D. et al. J Clin Oncol; 24:2098-2104 2006
Copyright © American Society of Clinical Oncology
Prognostic value of F-MISO PET
Rajendran, J. G. et al. Clin Cancer Res 2006;12:5435-5441
Copyright ©2006 American Association for Cancer Research
Tumour hypoxia,
does it matter?
The clinical importance of tumor hypoxia
1. Resistance to radiotherapy
2. Resistance to chemotherapy
3. Contribution to ‘malignancy’
Cure = min kill of 109 cells
Cure = min kill of 109 cells
90% cell death: Partial Remission, no cure
99,9% cell death: Complete remission, no cure
99,9999999% cell death: Complete remission, Local
control, Cure if no metastasis
Cell death N°1 = Mitotic death
Stem cells?
Dividing cells
Unfit cells
First clinical demonstration of hypoxia-mediated
radioresistance
1909
Gottwald Schwarz
Vienna
1880-1959
In vitro effect of hypoxic conditions
on radiation-induced cellular lethality
10
OER (Oxygen enhancement ratio)
= Radiation dose in hypoxia/ Radiation dose in air
Surviving fraction
1
0.1
OER = 2.8
0.01
oxic
Hypoxic
0.001
0
5 10 15 20 25 30
Radiation dose (Gy)
Cells are much more sensitive to x-rays in the presence of molecular oxygen than in its absence.
The ratio of doses under hypoxia to those under oxia necessary to produce the same level of cell
killing is close to 3.
G. Steel,
Basic Clinical Radiobiology 1997, second edition
Impact of hypoxia on survival in patients
with cervical cancer and definitive radiotherapy
Radiotherapy
1.0
pO2 > 10mmHg, n = 19
0.8
0.6
0.4
pO2 < 10mmHg, n = 23
0.2
Log-rank p = 0.0638
0
0
10
20
30
40
Time (months)
Höckel M. et al. Cancer Res 56, 4509-4515 (1996)
50
60
70
80
blood vessel
cytotoxic drug
resistance to radiation
drug
conc
Distance from vessel
Impact of pretreatment on prognosis in surgically
treated patients with cervical cancer
Overall survival
1.0
Surgery
0.8
pO2 > 10 mm Hg, n = 22
0.6
0.4
0.2
Höckel M. et al, 1996
pO2 < 10 mm Hg, n=25
Log-rank n = 0.0107
0
0
10
20
30
40
50 60
Time (months)
70
80
Treatment of hypoxic cells: One
example:
To kill hypoxic cells with a
“bioreductive drug”
Non toxic prodrug
Toxic drug
Hypoxia
Mechanism Tirapazamin
• Selectivity for tumors:
• in hypoxia: TPZ radical is formed
which causes DNA breaks
• in aerobic conditions: TPZ
radical is reoxidized towards the
parent compound with the
production of superoxide radicals
which are moderately cytotoxic
Exploit hypoxia: tirapazamine, a bioreductive drug
• Tirapazamine - a hypoxia selective cytotoxin
Tirapazamine, Cisplatin, and Radiation versus Fluorouracil, Cisplatin,
and Radiation in patients with locally advanced head and neck cancer: a
randomized phase II trial of the Trans-Tasman Radiation Oncology
Group (TROG 98.02). Rischin D et al. JCO 05 Jan 1;23(1):79-87.
Effect on normal
tissues
Rischin D et al. Tirapazamine,
Cisplatin, and Radiation versus
Fluorouracil, Cisplatin, and
Radiation in patients with locally
advanced head and neck cancer: a
randomized phase II trial of the
Trans-Tasman Radiation Oncology
Group (TROG 98.02). JCO 05 Jan
1;23(1):79-87.
Time to local failure (Kaplan-Meier method) by treatment arm and hypoxia in the primary
tumor (censored times are indicated as tick marks on the curves)
Rischin, D. et al. J Clin Oncol; 24:2098-2104 2006
extra 2 Gy
during the
same
fraction
2 Gy
Does hemoglobin has a prognostic value in
human cancer ?
Hb is associated with locoregional
control of head and neck cancer by RT
80
67.8%
Locoregional Failure (%)
65.9%
Low Hb
60
High Hb
51.6%
48.3%
40
20
p = 0.0026
Males Females
< 14.5 < 13.0 g/dl
 14.5  13.0 g/dl
Low Hb
High Hb
0
0
1
2
3
4
Years from randomization
5
6
7
Lee et al. (RTOG 85-27), IJROBP 42:1069, 1998
Overgaard (1988)
Squamous Ca larynx/pharynx
1112 patients
Oxidative damage:
Plays a role in carcinogenesis
Tumour Hypoxia:
- related to treatment resistance
- related to tumour aggressiveness
BUT ALSO
- a unique therapeutic opportunity!