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

1 mm size

Normal colon Abnormal vasculature is a prime cause of hypoxia in cancer Corrosion castings Colon xenograft Tumor hypoxia

Two types of hypoxia

oxygen glucose conc Distance from vessel blood vessel

Heterogeneity in Oxygenation a)Amount (%) amongst patients b)In severity c)In space d)In time

Hypoxia tolerance/angiogenesis

Hypoxia tolerance varies amongst tumors

oxygen glucose conc Distance from vessel blood vessel

Tumour hypoxia, does it exist in human tumours?

Nordsmark et al. Acta Oncol 1994 pO 2 measurements indicate most tumors are hypoxic Oxygen partial pressure (mmHg) Normal tissue Relative frequency (%)

Median Oxygen Levels of Human Tumors Tumor TypeMedian pO 2 (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 Lung12.8 (26 pts)Le & Stevens (pers. comm.) Breast10.0 (15 pts)Vaupel et al, 2002 Pancreas 2.7 (7 pts)Koong et al, 2000 Cervix10.0 (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 Cf. normal = mmHg

Rischin, D. et al. J Clin Oncol; 24: (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.

Copyright ©2006 American Association for Cancer Research Rajendran, J. G. et al. Clin Cancer Res 2006;12: Prognostic value of F-MISO PET

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 10 9 cells

90% cell death: Partial Remission, no cure 99,9% cell death: Complete remission, no cure 99, % cell death: Complete remission, Local control, Cure if no metastasis

Cell death N°1 = Mitotic death Stem cells? Dividing cells Unfit cells

1909 Gottwald Schwarz Vienna First clinical demonstration of hypoxia-mediated radioresistance

G. Steel, Basic Clinical Radiobiology 1997, second edition In vitro effect of hypoxic conditions on radiation-induced cellular lethality 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. OER = 2.8 Hypoxic oxic Surviving fraction Radiation dose (Gy) OER (Oxygen enhancement ratio) = Radiation dose in hypoxia/ Radiation dose in air

Impact of hypoxia on survival in patients with cervical cancer and definitive radiotherapy pO 2 < 10mmHg, n = 23 pO 2 > 10mmHg, n = 19 Radiotherapy Time (months) Overall survival probability Log-rank p = Höckel M. et al. Cancer Res 56, (1996)

cytotoxic drug drug conc Distance from vessel blood vessel resistance to radiation

Impact of pretreatment on prognosis in surgically treated patients with cervical cancer Höckel M. et al, 1996 Overall survival Surgery pO 2 > 10 mm Hg, n = 22 pO 2 < 10 mm Hg, n=25 Log-rank n = Time (months)

Treatment of hypoxic cells: One example: To kill hypoxic cells with a “bioreductive drug” Non toxic prodrugToxic 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.

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): Effect on normal tissues

Rischin, D. et al. J Clin Oncol; 24: 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)

2 Gy extra 2 Gy during the same fraction

Does hemoglobin has a prognostic value in human cancer ?

Hb is associated with locoregional control of head and neck cancer by RT Lee et al. (RTOG 85-27), IJROBP 42:1069, Years from randomization MalesFemales Low Hb< 14.5< 13.0 g/dl High Hb  14.5  13.0 g/dl 48.3% Low Hb 51.6% 65.9% 67.8% High Hb p = Locoregional Failure (%)

Overgaard (1988) Squamous Ca larynx/pharynx 1112 patients

Tumour Hypoxia: - related to treatment resistance - related to tumour aggressiveness BUT ALSO - a unique therapeutic opportunity! Oxidative damage: Plays a role in carcinogenesis