2. THERAPEUTIC RATIO
• The ratio between the doses that produce
the same level of antitumour efficecy(TCP)
and normal tissue damage(NTCP)
3. RADIOSENSITIZATION
1. Augmentation of tumour Oxygenation.
2. Sensitization of Hypoxic cells.
3. Pharmacologic targeting of hypoxic cells.
4. Hyperthermia.
5. Chemotherapy.
6. Biological modifiers.
4. THEOXYGENEFFECT
• A Well-Oxygeneted cell (PO₂>10mmHg) is about 2.5
times more sensitive to a given dose of radiation than
their hypoxic counterparts.
• Tumour hypoxia is strongly correlated with-
– Both infield Rx failure & OS in H&N malignancies.
– Local & distal recurrence in Ca Cx(Rx with Sx/RT).
– Distant failure in STS (Rx with Sx & Adj RT).
5. 1.Augmentation of Tumour Oxygenation
METHODS PROS CONS COMMENTS
Hyperbaric O₂ Benefit in Cx,H&N No benefit-
CNS,Lung,UB,skin.
Cumbersome,no
routine use.
Carbogen(95%O₂,
5%CO₂)+/̶nicotina
mide
↑Tx oxygenetion
in some Pt.s
No benefit on trials no routine use.
ARCON Better 5yr regional
control
Nicotinamide
induced
nausea,vomiting.
No dif in local cntrl
Tx c high hypoxic #
benefitted only.
Efaproxiral(RSR13) ↑MS in Ca Breast
c Brain Mets
No survival benefit
Anaemia
correction
• BT
• Erythropoietin
BT-Initial study ↑
pelvic control &
cure rates
BT-no survival
benefit
EPO-↓OS in
H&N,↑TE ,More
nvasive Ds.
6. 2.SENSITIZATION OF HYPOXIC CELLS
• e¯ affinic compounds can oxidize RT induced free radical damage→
↑kill.
• Agents-
– Misonidazole
• DAHANCA2-No significantly better Tx control.
• EORTC-No diffrence in Rx outcome.
• Serious peripheral neuropathy.
– Etanidazole
• Lower lipid solubility.
• Less neurotoxic.
• RTOG-Survival was 43% only compared to 41% (RT alone)
• A europian trial- no ↑benefit.↑neurotoxicity.
7. – Nimorazole
• Emetogenic.
• DAHANCA- ↑Locoregional control,No survival
benefit.
• Another study-↓locoregional failure (trial was
underpowered).
• SOC in Denmark only.
• NIMARD-Result yet to come.
8. 3.PHARMACOLOGIC TARGETING OF HYPOXIC
CELLS
• MitomycinC-
– Metabolized in ↓PO₂ regions.
– Integral role in Ca Anal canal c RT & %5FU.
– Yale University research (in H&N RT c MMC)
a. Locoregional recurrence free survival ↑
b. Marginal ↑ OS.
– University of vienna research
V-CHART
+MMC
V-CHART CF
LOCOREGIONAL
CONTROL
48% 32% 31%
SURVIVAL 41% 31% 24%
9. • Porfiromycin-
– Derivative of MMC.
– Greater differential cytotoxicity between hypoxic
& oxygeneted cells.
– Yale University research-
• MMC is superior to porfomycin in all respects. (i.e 5yr
relapse free survival,locoregional relapse free survival,
disease free survival).
• No significant diffrence in OS,Distant mets free rate.
10. • Tirapazamine –
– Bioreductive agent-preferential cytotoxicity to hypoxic
cells.
– In hypoxic condition a free radical 1 e¯ product is
formed→damages pyrimidine→DSB.
– ↑Cytotoxicity of cisplatin.
– Rischin et al –
• found Rx efficecy in Tirazapamine arm against tumour
hypoxia.
– HeadSTART-
• No difference in failure free survival,time to locoregional
failure & QOL.
11. 4.HYPERTHERMIA
• Elevation of tissue temp. (40-45°C)for a therapeutic effect.
• Mainly acts by ↑reoxygenation.
• Also interfere with RT induced radiation damage.
• TER-Ratio of RT dose without HT to the isoeffective RT dose for
equivalent effect with HT.
• Clinical trials yeilds mixed response.
• Some metaanalysis-↑response in H&N and Ca Cx.
• Dutch Deep Hyperthermia Group-
– ↑CR
– ↓Death rates.
• Due to technical difficulty of homogeously heating a tumour, this
strategy has lost popularity.
12. 5.CHEMOTHERAPY
• Goal is to Improve survival by
– ↑locoregional control.
– ↓/eliminate distant mets.
• Strategies- (Steel & Pekham)
1) Spatial cooperation.
2) Independent toxicity.
3) Enhancement of tumour response.
4) Protection of normal tissues.
17. b)Molecular signaling pathways that may be responsible for
radioresistence.
c)Targetting tumour microenvironment
d)Cancer stem cells.
e)Induce immunogenic cell death pathway.
f)Improving systemic therapy outcome by cytoreduction of gross
mets c SBRT
19. SPECIFIC CHEMOTHERAPIES
A.Platinum based drugs-
1) MOA-
a. ↓DNA synthesis.
b. ↓transcription elongation by DNA interstrand
crosslinks.
c. ↓repair of RT induced DNA damage.
2) Agents -
1) Cispltin
2) Carboplatin
3) Oxaliplatin
20. B. Antimicrotubules
• Taxanes-
1. MOA-
Cell cycle arrest in G2M phase.
Induction of apoptosis.
Reoxygenetion of tumour cells.
2. Agents-
Paclitaxel
Docetaxel.
Other novel congeners –Abraxane ,paclitaxel
poliglumex,Iarotaxel,Cabazitaxel,Oral taxanes.
21. C. ANTIMETABOLITES
• 5-FU-
MOA-
1. Incorporation into RNA →disruption of RNA
function.
2. ↓Thymidylate synthase→ ↓DNA synthesis.
3. Direct incorporation into DNA.
• Capacitabine-
Oral prodrug of 5FU.
Thymidine phosphorylase play pivotal role in
conversion.
22. • Gemcitabine-
MOA-
1. Incorporation into DNA→perturbation of nucleotide pool.
2. ↓apoptotic threshold.
3. Cell cycle redistribution.
4. Tumour cell reoxygenetion.
• Pemetrxed –
MOA-
1. ↓multiple folate requiring enzymes.
2. Interfers c DNA synthesis.
3. ↑apoptosis(may be).
23. D. Topoisomerase I inhibitors
• MOA
1. ↓Repair of RT induced DNA strand breaks.
2. Redistribution into G2 phase.
3. Converting RT induced SSB’s→DSB’s.
• Agents-
1. Camptothecin.
2. Irinotecan.
3. Topotecan.
4. 9-aminoCamptothecin.
5. SN-38.
24. E. Alkylating agents
• Temozolamide-
– Crosses BBB.
– ↑radioresponse in MGMT –ve glioblastomas.
– MOA
• ↓DNA repair.
30. RADIOPROTECTORS
• Radioprotectors- prophylactic agents
administered prior to radiation exposure to ↓
cellular & molecular damage.
• Radiation mitigators- drugs administered
shortly after irradiation,but prior to the
manifestation of normal tissue toxicity to↓the
severity of the radiation response.
• Radiation therapeutics- agents given after
overt symptoms appear in order to stimulate
repair/regeneration.
31. DISCOVERY
• Heart of radioprotectors is SULFHYDRYL
(SH) group.
• PATT (in 1948) –Discovered Cysteine.
• BACQ et al - Discovered Cysteamine.
36. SEARCH FOR MORE
EFFECTIVE COMPOUNDS
• 1959- US army started research @Walter Reed
Institute of Reseach.
Cystaphos- Used by USSR during cold war.
Amifostine- Used by US in lunar mission.
37. ..but
VERY LIMITED ROLE IN
NUCLEAR TERRORISM
1. Must be administered before exposure.
2. A/E –nausea , vomiting,transient
hypotension.
3. Extremely short window of activity.
4. I.V route.
39. OTHER AGENTS..
• AMINOTHIOLS(PrC-210)
a. Better eficacy.
a. Small size.
b. +ve charged.
c. Perpendicular,alkyl side chains.
b. 100% survival in murine models.
c. No retching,emesis or hypotension.
d. Primate study yet to be done.
43. IN THE PIPELINE…
1. A Steroid.
2. An isoflavone.
3. A truncated flagellin protein.
4. A novel kinase inhibitor.
5. Recombinant human interleukin(IL)-12.
6. A dipropionate.
7. A growth factor.