1. Oxygen and Cancer: friend or foe?

2. Part 1: Scientific part Dirk de Ruysscher Part 2: Organisational part Harald Moonen

3. Cancer = Genetic disease with 6 features

4. The 6 Hallmarks of Cancer

5. HYPOXIA = LACK OF OXYGEN

6. Tumor hypoxia Hypoxia

7. 1 mm size

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

9. Two types of hypoxia

11. oxygen glucose conc Distance from vessel blood vessel

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

13. Hypoxia tolerance/angiogenesis

14. Hypoxia tolerance varies amongst tumors

15. oxygen glucose conc Distance from vessel blood vessel

16. Tumour hypoxia, does it exist in human tumours?

17. Nordsmark et al. Acta Oncol 1994 pO 2 measurements indicate most tumors are hypoxic Oxygen partial pressure (mmHg) 020406080 0 5 10 15 20 Normal tissue Relative frequency (%)

18. 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 = 30-60 mmHg

19. Rischin, D. et al. J Clin Oncol; 24:2098-2104 2006 (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.

20. Copyright ©2006 American Association for Cancer Research Rajendran, J. G. et al. Clin Cancer Res 2006;12:5435-5441 Prognostic value of F-MISO PET

21. Tumour hypoxia, does it matter?

22. The clinical importance of tumor hypoxia 1.Resistance to radiotherapy 2.Resistance to chemotherapy 3.Contribution to ‘malignancy’

23. Cure = min kill of 10 9 cells

24. 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

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

26. 1909 Gottwald Schwarz Vienna 1880-1959 First clinical demonstration of hypoxia-mediated radioresistance

27. 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 501510252030 0.001 0.01 0.1 1 10 Surviving fraction Radiation dose (Gy) OER (Oxygen enhancement ratio) = Radiation dose in hypoxia/ Radiation dose in air

28. 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) 1.0 01020304050607080 Overall survival probability Log-rank p = 0.0638 0.8 0.6 0.4 0.2 0 Höckel M. et al. Cancer Res 56, 4509-4515 (1996)

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

30. 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 = 0.0107 1.0 0.8 0.6 0.4 0.2 0 01020304050607080 Time (months)

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

32. 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

33. Exploit hypoxia: tirapazamine, a bioreductive drug Tirapazamine - a hypoxia selective cytotoxin

34. 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.

35. 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. Effect on normal tissues

36. Rischin, D. et al. J Clin Oncol; 24:2098-2104 2006 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)

37. 2 Gy extra 2 Gy during the same fraction

38. Does hemoglobin has a prognostic value in human cancer ?

39. Hb is associated with locoregional control of head and neck cancer by RT Lee et al. (RTOG 85-27), IJROBP 42:1069, 1998 80 60 40 20 0 Years from randomization 0 1 2 3 4 5 6 7 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 = 0.0026 Locoregional Failure (%)

40. Overgaard (1988) Squamous Ca larynx/pharynx 1112 patients

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