5. • Tumor hypoxia reduces radio sensitivity in vitro and in vivo.
Well oxygenated cells (partial pressure of oxygen or Po, >10
mm Jig)are approximately 2.5 times more sensitive to a given
dose of ionizing radiation than their hypoxic counterparts.
6. • The correlation between pretreatment head and neck tumor
oxygenation and local-regional disease control after radiotherapy with
or without concurrent chemotherapy.Dashed line represents tumor
median partial pressure of oxygen PO2 >10 mm Hg,Solid line represents
tumor median PO2 <10 mm Hg,
7. III
increased delivery of oxygen to tumor
Augmentation of tumor oxygenation
preferential sensitization of hypoxic cells
with oxygen mimetic agents
preferential sensitization of hypoxic
cells with cytotoxic agents that
selectively target hypoxic tumor cells
I
II
Therapeutic attempts to overcome the
deleterious effect of tumor hypoxia have
followed three general lines of Investigation:
8. Hyperbaric oxygen(HBO)
Clinical trials of hyperbaric oxygen (HBO)
and RT were conducted from the 1950s
to the 1970s.
Lung, bladder and
skin
carcinoma of the
cervix and head
and neck
show no benefit
show improvements
in locoregional
control and overall
survival.
10. • 20% improvement in 2-year local control in
the carbogen arm relative to the RT alone
arm.
• 15% improvement in a -year cause-specific
survival.
• hyperfractionated RT with or without
carbogen
• patients with T2 to T4 squamous cell
carcinoma of the oropharynx. larynx. and
hypopharynx
•TERIAL 1:University of Florida
11. • The use of accelerated RT with carbogen and
nicotinamide
• In 215 head and neck cancer patients
Terial2:
cancer Five-year locoregional control
rate
hypopharynx primaries 48%
larynx 77%
oropharynx primaries 72%
12. Ways for correction or prevention of
anemia:
• blood transfusions
• erythropoiesis-stimulating agents
anemia
13. • in cervical cancer patients:
showing an improvement in pelvic control and cure
• In head and neck cancer patients:
negative effect on surviva1.
Blood transfusions
14. • Misonidazole:the prototype2-nitroimtdazole.
• Etanidazole (SR2508):an analog of
misonidazole
• Nimorazole: a 5-nitroimidazole of the same
structural class as metronidazole.
Sensitization of hypoxic cells
15. • 1.Mitomycin C (MMC)
• 2. Porfiromycin:a derivative of MMC
• 3. Tirapazamine
Pharmacologic targeting of
hypoxic cells
16. • Mitomycin C (MMC) is an alkylating agent
metabolized in regions of low oxygen
concentration and preferentially cytotoxic to
hypoxic cells. MMC plays an integral role in
conjunction with RT and 5-FU (fluorouracil) in
the definitive non surgical management of
squamous cell carcinomas of the anus.
1.Mitomycin C (MMC)
17. • Terial1:
• 195 head and neck cancer patients
• 68 Gy with or without MMC on days 1 and 43 of RT
•1.Mitomycin C (MMC)
RT+MMC RT
Local regional
recurrence-free
survival
76% 54%
Overall survival 48% 42%
18. • Terial2:
• conventionally fractionated (CF) RT (2 Gy daily to 70
Gy) against variation of continuous
hyperfractionated accelerated RT with or without
MMC
•1.Mitomycin C (MMC)
V-CHART+MMC V-CHART CF RT
Three-year actuarial
locoregioal control
48% 32% 31%
Surv ival including death
from all causes
41% 31% 24%
mucositis 90% 90% 33%
