2. INTRODUCTION
■ Radiation is a loco-regional therapeutic modality used in definitive or palliative
management of approximately two third of cancer patients
■ Cellular DNA molecule of cancer cells or normal tissues is the target for radiation
■ DNA damage to cancer cells via:
• Direct damage photon electron damage the DNA.
• Indirect damage photon electron generate free radical damage the
DNA.
● Single broken strand can usually be repaired by the cell while two broken strand
commonly results in cell death
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4. Therapeutic Ratio
Ratio of Tumor lethal dose /Normal tissue
toxicity
TR is a indicates if a tumor is radio-curable
TLD> NTT then radical dose of radiation
cannot be delivered radioresistant
The optimum choice of radiation dose delivery
technique is one of the maximizes the TCP &
simultaneously minimize the NTCP
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5. How to achieve tumor
control ?
1. Dose escalation
2. Reduce the dose to
normal tissue
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6. Dose escalation
■ Physical &Technological techniques: Conformal radiotherapy
■ Exploiting Radiobiological advantages: fractionation & Quality of radiation
■ Chemical agents- radiosensitizers & chemical radioprotectors
■ Others- stem cell therapy, gene therapy
Protection of
normal tissue
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7. To deliver sufficient
dose to the tumor
To induce minimal damage
to the in the surrounding
normal tissue
Probability of
cure
Risk of
toxicity
Need of Radiation Modifiers
The tolerance of normal tissue continues to limit the maximum dose that can
be delivered safely to the tumor
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8. Radiation modifiers
• Agents that can modify the sensitivity of tumor or normal tissue to
radiation are collectively called as radiation modifiers
• They should increase possibility of tumor control without increasing the
normal tissue injury
● Radiation sensitizer increase the effect of RT, selectively on the tumor
● Radiation protector spares Normal tissue from effects of RT
● Radiation mitigators Prevent occurrence of detrimental effects of RT on
normal tissues
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9. Therapeutic ratio with radiation sensitizer
RS Shifts the tumor control curve to the left
Resulting in higher chances of cure for an equivalent
toxicity
Selective uptake in tumor leaky tumor vasculature or
pathways targeted by the radiation sensitizer or
receptors affected by the RS may have
higher/preferential expression in tumor
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10. Therapeutic ratio with radiation protector
Radioprotector reduces the probability of normal
tissue toxicity for a given dose of radiation
Pushing the toxicity curve to the right
Allows higher dose to be delivered
Higher rate of cure with less or equivalent normal
tissue injury
Selective uptake of RP in normal tissue through
enhanced delivery, uptake or retention compared with
tumor and this give greater protective effective in
normal tissue
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11. Expresses the response of the tumor to irradiation
BERGONIE & TRIBONDAEU’S LAW:
Tissue is considered radiosensitive when
● The cells are undifferentiated
● High metabolic activity
● Higher proliferative capacity and high growth rate
Radio-curability- is the ability of radiotherapy to cause the local eradication of a malignancy
E.g. : Leukemias- these are radio sensitive tumor but not radio-curable
RADIOSENSITIVITY
Exquisitely RS - Small cell lung cancer,
Germ cell tumor, Lymphoma
Moderately RS –Breast cancer, Non small
cell lung cancer, Breast cancer
Radioresistant – Malignant melanoma,
Renal cell carcinoma, adenocarcinoma
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13. Cell cycle phase & Radiosensitivity
M>G2>G1>EARLY S>LATE S
G1
S
G2
M
G0
G0
MITOSIS
DNA
SYNTHESIS
2nd
GAP
1st GAP
RADIORESISTANT
MOD
RADIOSENSITIVE
HIGHLY RADIOSENISTIVE
G1
S
G2 M
Checkpoint inhibitors
CDK2/ CYCLIN
CYCLINE/CDK
2
CYCLIND/
CDK4
CYCLIN
B/CDK1
15. Oxygen effect in Radiotherapy
● After absorption of radiation interaction
with water molecules free radical
production occurs
● passing through biological material these
induce SSBs and DSBs however short
lived
● O2 causes oxidation fixation of these
breaks causing unrepairable DNA damage
This is called “damage fixation” by oxygen
16. Oxygen Enhancement Ratio
OER- Dose to produce a given effect with no O2 present
Dose to produce the same effect with 1 atm of air
■ Oxygen is the best known most general radiation sensitizer
■ Well oxygenated cells- approximately 2.5 times more sensitive to a given dose of
ionizing radiation
■ Its value close to 3.5 at high doses but may have lower value of about 2.5 at x-ray
less than about 2 to 3 Gy
17. HYPOXIA
● CHRONIC HYPOXIA- Limited diffusion
distance of O2 through tissue
● ACUTE HYPOXIA- Temporary closing of a
tumor blood vessel owing to the malformed
vasculature of the tumor due to lack of
smooth muscle, incomplete endothelial lining
and incomplete basement membrane
● Leads to slow rate of proliferation which
decreases the sensitivity to chemotherapy and
radiotherapy
● The concentration of anticancer drugs lesser
in cells away from the blood vessels leads to
COP-
22mmhg
COPi- 20
mmhg
PP- 0
mmhg
70um
18. IDEAL RADIOSENSITISER
■ Non-cell cycle specific
■ Potent radio sensitizing effect
■ Lack of toxicity
■ Adaptable to convenient out-patient administration
To be clinically effective they should improve the therapeutic ratio i.e.
TCP/NTCP, because if it equally increases the effect and side effect
then it is not useful
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19. CHEMICAL
●Modifiers of HB
●Hypoxic cell and non hypoxic
cells radiosensitizer
●Hypoxic cytotoxins– non hypoxic
cell
●Biologic modifiers
●Chemotherapeutic drugs
PHYSICAL
●Hyperbaric oxygen
●Carbogen with or without
nicotinamide
●Arcon
●Hyperthermia
TYPES OF RADIOSENSITIZATION
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21. HYPERBARIC OXYGEN
■ HBO therapy- an increase in
barometric pressure of the gas breathed
by the patient during radiotherapy is
termed as hyperbaric oxygen therapy
■ Pioneered by Churchill-Davidson in
1958 at St. Thomas hospital in London.
■ Patients were sealed in chambers filled
with pure oxygen raised to a pressure at
3 atm
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22. ■ M.O.A.- enhances the amount of dissolved oxygen in plasma, thereby increasing
O2 delivery independent of hemoglobin
■ Elevation of the tumor oxygen pressure has ben shown to be preserved clinically
after 30 min after HBO exposure
■ Tissue damage is dependent on the cell type, concentration of O2 and duration of
exposure
■ Two different application in combination with radiotherapy
● As a radiosensitizer
● As a therapeutic agent for treating late radiation injury
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23. BOHR EFFECT
Hyperbaric oxygen shift the graph to the
right side , so more unloading at the
metabolizing site ( tumor site) due to low Ph
in the environment
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24. PROBLEMS
● Feeling of claustrophobia from being sealed in narrow tube
● Cumbersome logistics associated with delivery- unconventional hypo-fractionated schemes
SIDE EFFECTS
● Barotrauma to ears ,sinuses and lungs
● temporary worsening of myopia
● Acute CNS oxygen toxicity
Recent Cochrane review- For H&N cancer, HBOT improved local tumour
control and tumour related mortality; No benefit in other subsites, rather
increased risk of severe radiation tissue injury observed
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25. CARBOGEN = 95% O2 + 5% CO2
● Pure oxygen if breathed vasoconstriction defeats the objective of increasing O2
availability
● RATIONALE addition of co2 to gas breathing mixture shift the oxygen-HB CURVE to
right which facilitate oxygen unloading into the tissue
● Corrects Chronic hypoxia
■ Advantages Can be given under normo-baric condition
Can be given with or without concurrent administration of nicotinamide
■ Clinically failed to provide significant therapeutic gain ( Horseman et al-2007)
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26. NICOTINAMIDE
■ Vitamin B3
■ Prevents the transient fluctuations in tumor blood flow corrects acute hypoxia
■ Nicotinamide administered 1 to 1.5 hrs prior to radiotherapy at 60-80 mg/kg
■ Acts as PARP inhibitor inhibits DNA repair
Synergistic effect seen in combination with
1. Hyperthermia
2. Perfluorochemical emulsion
3. Pentoxifylline
4. High oxygen content gas breathing
BCON- Study shows continued a benefit from hypoxia
modification using a carbogen and nicotinamide with
radiation therapy in bladder cancer in presence of necrosis, a
high hypoxia gene score and the basal type
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27. ARCON
Combination of altered fractionation and radiosensitisation using carbogen and nicotinamide
● Accelerated- to overcome proliferation
● Hyper-fractionated - to spare late responding normal tissues
● Carbogen breathing- to overcome chronic hypoxia
● Nicotinamide- to overcome acute hypoxia
RESULT INDICATE THAT ADVANCED LARYNGEAL CANCER WHEN COMBINED
WITH
ARCON HAS A LOCOREGIONAL CONTROL RATE 92% AND EXCELLENT
POSSIBILITIES FOR LARYNGEAL PRESERVATION
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28. HYPERTHERMIA
■ Definition : Elevation of temperature to a supra-physiologic level in the
range of 39 C TO 45 C
■ Hippocrates (470-377 BC) states- “ What medicines do not heal, the lance
will; what the lance does not heal, fire will. Those who cannot be cured by
fire, they are indeed incurable”
■ Biological basis of hyperthermia is based on : Classic radiobiology,
molecular biology and tumor physiology
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29. Hyperthermia induced Cytotoxicity
■ Log linear cell kill very similar to ionizing
radiation cell kill
■ Shoulder region followed by steep slope
■ Lower temperatures, a tail is seen suggestive
of resistant fraction of cells– Thermotolerance
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30. THERMAL ISOEFFECT DOSE:THE ARRHENIUS
RELATIONSHIP
■ Temperature dependence of the rate of cell killing by
heat portrayed by Arrhenius plots
■ Plots the log of the slope (1/Do) of cell survival
curves as a function of temperature
■ Biphasic curves with slope changes at the BREAK
POINT (43 degree for human cells)
■ Above this temperature, an increase of 1 C double the
rate of cell killing
■ Below the breakpoint, the rate of cell killing by heat
drops by a factor of 2 to 4 for each drop of 1 C
■ Cumulative equivalent minutes at 43* C (thermal
dose)
CEM 43 = tR(43-T)
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31. THERMOTOLERANCE
■ Development of a transient and
nonhereditary resistance to subsequent
heating by an initial HT
■ Begins a few hours after the first treatment
and takes up to a week to decay
■ Shift the Arrhenius curve to the right and
downward, reflect great thermal resistance
to heat
■ Clonogenic assays reveal that although one
dose of heat kills a substantial fraction of
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32. MECHANISM OF ACTION
DIRECT EFFECTS
■ Target for hyperthermia is protein
■ Denaturation of other proteins takes place with HT
■ Heat shock protein upregulation occurs with HT
■ Cytoskeleton of cell i.e., membranes disrupted and signaling pathways are impaired
■ DNA repair proteins are damaged
■ Centrioles are denatured leading to chromosome aberrations
TUMOR CELL DEATH
1. APOPTOSIS reoxygenation due to cell loss
2. NECROSIS
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33. Physiology of HT
EFFECT on pH
Tumor cells
Decrease in extracellular PH
Cannot increase proton pumping
Increase in intracellular PH and lead
increase in cyto-toxicity
IMMUNOLOGICAL
EFFECT
■ Heat shock proteins are expressed in cell
surface after hyperthermia
■ Antigen presentation to dendritic cells
■ HSP70 as a cytokine produce
proinflammatory cytokines via binding to
CD14
■ So monoclonal antibodies can be made
for monitoring these proteins non
invasively
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34. EFFECT ON
PERFUSION
Increased tissue perfusion (41-41.5 C)
Changes in vascular permeability
Vascular stasis and hemorrhage (42-44C)
EFFECT OF HYPOXIA
Hypoxic cells are not resistant to
hyperthermia as opposed to X rays
which are not effective against
Hypoxic cells
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35. Based on mode of delivery of hyperthermia, classified as
● Local hypothermia
● Regional hyperthermia
● Whole body hyperthermia
Clinical hyperthermia achieved by exposing tissue to-
■ Conductive heat sources
■ Non-ionizing radiation e.g.- electromagnetic or ultrasonic waves
Can be administered using-
■ Invasive sources-radiofrequency antennas, RF electrodes, ferromagnetic metals & US
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37. RATIONALE FOR COMBINATION WITH
EXTERNAL RADIOTHERAPY
● Sensitizes the cells in S phase to RT
● No difference in sensitivity to aerobic and anaerobic cells
● HT can lead to reoxygenation which will improve RT response
● HT inhibits the repair of both sub lethal and potentially lethal damage via
its effects in inactivating crucial DNA repair pathways
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38. RATIONALE IN CHEMOTHERAPY
● Increased oxygen radical production
● Hypoxia and pH changes reverse drug resistance
● increased cellular uptake of drug damaged cell membranes enable perfusion independent
drug uptake into tumor tissue
● Temperature sensitive liposome used to selectively deliver drug to tumors because
hyperthermia increases drug delivery and efficacy. E.g. doxorubicin liposomes low
temperature sensitive formulation that exhibits very rapid release of drug ( 50% of drug
release when temperature reaches at 40 degree C
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39. THERMAL ENHANCEMENT RATIO
■ Is defined as the ratio of doses of X-
rays required to produce a given level
if biological damage with and without
the application of heat.
■ TER decreases with increasing time
interval between heat and RT
■ TER increases with increasing heat
dose
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40. ■ Typical TER values applied for 1 hour
● 1.4 at 41 degree
● 2.7 at 42.5 degree
● 4.3 at 43 degree
■ When RT precedes HT,sensitization no longer detectable 2-3 hrs after RT
■ When HT precedes RT, cells can be sensitized for upto several hours
THERAPEUTIC GAIN FACTOR
Ratio of the TER in the tumor to the TER in normal tissues
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41. ADVERSE EFFECTS
■ External application of heat may cause surface burns
■ Whole body hyperthermia can cause swelling , blood clots and bleeding
■ Systemic shock
42. ●META ANAYLYSIS- Showed small but significant benefit of
sensitizer in local control and overall survival which was
shown in head & neck ,bladder & rectal cancer but non-
significant benefit in prostate & breast cancers
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43. CHEMICAL RADIOSENSITISERS
●Modifiers of HB
● Non hypoxic cell radiosensitizer
●Hypoxic cell radiosensitizer
●Hypoxic cytotoxins
●Biologic modifiers
●Chemotherapy
44. BLOOD
TRANFUSION
■ Anemia, powerful adverse prognostic
factor in pts of ca cervix, H & N cancers &
lung cancer
■ 1ST clinical investigation- in advanced
cervical cancer
■ Transfusion to HB level of 11 mg/dl or
higher- improved survival
■ Transfusion to HB level of 11g/dl or
higher- improved survival
■ Transfusion to pts with low Hb levels lead
to increased oxygen tension within tumor
In a study of Denmark, the patients with low
hemoglobin level had a significant reduced
probability of locoregional control, disease-
specific and overall survival. In the low
hemoglobin group, transfusion did not
improve the outcome in locoregional control,
disease specific or overall survival
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45. ERYTHROPOETIN
It is an alternating means of raising hemoglobin during radiotherapy
● Dose- 200 micro/kg/day * 5 days/week
● Not cost effective(vs. transfusion)
● Induces prompt reticulocyte count
● Two studies conducted in head & neck cancer failed to show any benefit
PERFLUROCARBONS
● Artificial blood substances
● Small particles capable of carrying more oxygen or manipulating the oxygen
unloading capacity of blood
E.g. Perfluorotributylamine
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46. NON-HYPOXIC CELL SENSITIZERS
● Halogenated pyrimidines
● Since rapidly dividing tumor cells require nucleotide metabolites for DNA synthesis, selective
uptake occurs compared to normal tissue
● MOA- Incorporates into DNA in place of thymidine faulty DNA more sensitive to U.V. Rays
and X-rays cell kill at attempted repair
● Cell cycle specific radiosensitizers
1. 5- bromodeoxyuridine
2. 5-iododeoxyuridine
● Tumor responses are good, but normal tissue toxicity was unacceptable because ofsusceptibility
of rapidly dividing cells like mucosa , skin , bone marrow which lead to more normal tissue
toxicity
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47. HYPOXIC CELL RADIOSENSITIZERS
● Electrophilic agents enhances the tissue response to standard radiation,
generally by mimicking the effects of oxygen, which induces the
formation and stabilization of toxic DNA radicals
● These are the nitroimidazole group of compounds and acts as electron
donors and reacts with DNA to form adducts with increased free radicals
and increased DNA damage
● Forms DNA adducts and increased free radicals
● Selectively activated in the hypoxic tumor cells causing
radiosensitisation with acceptable normal tissue toxicity
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48. PROPERTIES OF HYPOXIC CELL SENSITIZER
■ Should be chemically stable & not subject to rapid metabolic break down
■ Highly soluble in water or lipids & must be capable of diffusing a considerable
distance through a non vascularized cell mass to reach the hypoxic cell
■ It should be effective at relatively low daily dose/fraction used in conventional
fractionated radiotherapy
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49. DOSE MODIFICATION
FACTOR
Defined as the dose of radiation required
to produce an effect without and with a
dose of radiation required to produce an
effect without and with a drug
DMF=
If DMF, =1 no drug effect
>1 enhancement
Dose (radiation)
Dose ( radiation+ drug)
SENSITIZER
ENHANCEMENT RATIO
■ The magnitude of sensitizing effect
is usually expressed as sensitizer
enhancement ratio for the same
biological effect
● None of the hypoxic sensitizers
developed to date can create more
SER= Radiation dose without sensitizer
Radiation dose with sensitizer
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50. than SER of 1.3 at tolerable doses
METRONIDAZOLE
■ 1st generation 5-nitroimidazole
■ Sensitizer enhancement ratio 1.2
■ Dose-oral 500mg tablets
■ Half life-9.8hrs
■ Total cumulative dose should not exceed
54gm/m2
■ Optimal time for administration – 4hr
before radiation
■ Dose limiting toxicity-
1. Gastrointestinal
2. Sensory peripheral neuropathy
MISONIDAZOL
E
● 2ND generation 2-nitroimidazole
● Higher electron affinity
● Sensitizer enhancement ratio
1.4 with multiple dose of 2gm/m2
1.15 with 0.5mg/m2
● Formulations 500 and 100 mg tab and
capsules
● Once or twice a week for 5-6 weeks
● Total cumulative dose not to exceed
12gm/m2
● Optimal dose for administration- 4hr
before radiation
51. ETANIDAZOLE
● 3RD generation analog of misonidazole
● SER- 2.5-3 with dose of 12 gm/m2
● 1000mg/19.4ml saline solution
● Total dose -40.8 g/m2 3 times/week for
6 weeks
● 30 min before radiation
● Arthralgia seen more often with 48 hr
continuous infusion
● Lesser neurotoxicity due to shorter half
life and lower lipid solubility( less
rapidly taken by the neural tissue)
PIMONIDAZOLE
● 4- Nitroimidazole
● More potent than
Misonidazole
● Several- fold increase in
tumor concentration
● Maximum tolerated dose-
750mg/m2
● Dose limiting toxicity-
CNS manifesting as
disorientation & malaise
52. NIMORAZOLE
● A5-nitroimidazole of same structural class as metronidazole
● Administered in form of gelatin-coated capsules containing 500mg active
drug
● Given orally 90 min prior to irradiation
● Daily dose 1200mg/m2 body surface
● Total dose not exceed 40gm/m2
● Less effective radiosensitizer than misonidazole or etanidazole
● Less toxic, no cumulative neuropathy
● Large dose can be given
53. In Denmark, Nimorazole has become the part of the
standard RT in Head & Cancer quote study locally
advanced pharynx and supraglottic cancer RT vs RT with
nimorazole showed local control 49% vs 33 % and can
be given without major side effects
NEWER NITROIMIDAZOLES ARE:
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54. • Doranidazole
HYPOXIC CYTOTOXINS- Bio reductive Drugs
■ Killing of radioresistant hypoxic cells by selective undergoing intracellular
activation in low oxygen tensions
■ Overcome major cause of resistance of solid tumors – inadequate
oxygenation & drug delivery to tumor cells distant to blood vessel
QUINIONE
ANTIBIOTICS
➢ MMC
➢ PORIFIROMYCIN
➢ E09
BENZOTRIAZINE
DI-N-OXIDES
➢ TIRAPIZAMINE
➢ CHLORAMBUCIL N-
OXIDE
NITROAROMATIC
➢ MISONDIAZOLE
➢ Nicq-1
➢ Pr-104
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55. MITOMYCIN-C
■ Chemotherapy drug alkylating agent inhibits DNA-DNA cross linking
■ Cytotoxic to radioresistant hypoxic cells
■ Differential cytotoxicity between hypoxic and oxygenated cells
■ Dose limiting toxicity-cumulative myelosuppression
■ Clinical application backbone of definitive chemoradiation protocols
in squamous cell ca of the anal canal in conjunction with 5 FU (1000
mg/m2) C.I.
■ Dose – 10mg/m2 on Day 1 and 30
PORFIROMYCIN - A mitomycin C derivative
■ Provides greater differential cytotoxicity between hypoxic and
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56. TIRAPAZAMINE (sr 4233)
● Highly selective toxicity against hypoxic cells both in vivo & vitro
● MOA causes ds DNA breaks via the active compound which is a drug is reduced by intracellular
reductases to form highly reactive material produces both double & single strand break in DNA
● 25-200 times more drug is required to cause same amount of cell kill in aerobic conditions compared to
anaerobic conditions
● Dose-290mg/m2/d on day 2 of weeks 1.4. and 7 weeks with cisplatin 75mg/m2
● Tirapazamine can also enhance the cytotoxicity of the cisplatin
● S/E- nausea & muscle cramping
● Unlike the oxygen-mimetic sensitizers, tirapazamine mediated therapeutic enhancement occur both
when the drug is given before or after irradiation
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58. GOALS IN COMBINING CT WITH RT
■ Improving local-regional tumor control
■ Decreasing or eliminating distant metastases
■ Preserving organ or tissue integrity and function
■ To have independent toxicity
■ To enhance tumor radio response
59. Enhancement of tumor radio-response
● Induces cell death by causing direct DNA Damage
● Increases cell DNA susceptibility to radiation by altering SLD repair/PLD repair
Cell cycle redistribution & synchronization
● Moves cells into more sensitive phases of cell cycle (G2M)
● Blocks transition of cells and accumulates in G-2 to M TAXANES
● Kill radioresistant S phase cells E.g. Gemcitabine
Counteracting Hypoxia-associated tumor radio-resistance
Chemotherapy cell kill leads to lowering of the interstitial pressure the reopening of
previously closed capillaries reestablishment of blood supply Previously hypoxic cells
are closer to capillaries hypoxia negated
Prevents repopulation of tumor cells that occurs during the course of radiation when used
concurently
CHEMOTHERAPY &RADIATION INTERACTION
MECHANISMS
60. Four Strategies to improve Therapeutic Index
Steel and Peckham classified into four
groups
■ A spatial cooperation
■ Independent toxicity
■ Enhancement of tumor response
■ Protection of normal tissue
61. SPATIAL COOPERATION
■ Action of RT and CT drugs occurs at different anatomical sites
■ No interaction between the two modalities
■ Independent action of the two agents Localized tumors are treated radiation therapy, while
chemotherapeutic drugs are given to eliminate disseminated micro metastases
E.g., Early-stage breast cancer
INDEPENDENT TOXICITY
■ Combination of radiation and CT is better tolerated if drug with non-overlapping toxicities are
used
■ Two modalities can both be given at full dose.
E.g., avoiding MTX with brain RT/ or bleomycin with lung irradiation
PROTECTION OF NORMAL TISSUES
■ Technical improvement in radiation delivery
■ Administration of chemical or biological agents that selectively or preferentially protect normal
62. tissue against the damage by radiation or drugs e.g. Amifostine, which is radical scavenging agent
Enhancement of tumor response(Cytotoxic
Enhancement)
Interaction between drugs and radiation at the molecular ,
cellular or pathophysiologic level, resulting in antitumor
effect greater than would be expected on the basis of
additive actions
Can be explained by iso-bologram
➢ Between mode1 and mode 2 above ( additive
interaction)
➢ Above mode 1 – infra-additive interactiojn
➢ Below mode 2- supra-additive interaction
Mode 1
Mode 1
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63. Biological Cooperation
■ Independent targeting if subpopulations of cells within the tumor itself, as
some portion of the actual radiation target is resistant to radiation
■ So more prominent example for biological cooperation is hypoxic cell
cytotoxins such as tirapazamine which is most potent in anoxic conditions
Temporal Modulation
■ Drugs that impact tumor response in between fractions targeting repair,
reoxygenation, repopulation and redistribution
■ For e.g.- antiproliferative therapies could prevent accelerated repopulation
between fractions , conversely although DNA damage repair blockade may
66. STRATEGY ADVANTAGES DISADVANTAGES
SEQUENTIAL
CHEMORADIATION
• Least toxic
• Maximizes systemic
therapy
• Smaller radiation fields if
induction shrinks tumor
• Increased treatment time
• Lack of local synergy
CONCURRENT
CHEMORADIATION
• Shorter treatment time
• Radiation enhancement
• Compromised systemic
therapy
• Increased toxicity
• No cytoreduction of tumor
CONCURRENT
CHEMORADIATION
AND ADJUVANT
CHEMOTHERAPY
• Maximizes systemic
therapy
• Radiation enhancement
• Both local and distant
therapy delivered up front
• Increased toxicity
• Increased treatment time
• Difficult to complete
chemotherapy after
chemoradiation
INDUCTION
CHEMOTHERAPY AND
CONCURRENT
CHEMORADIATION
• Maximizes systemic
therapy
• Radiation enhancement
• Increased toxicity
• Increased treatment time
• Difficult to complete
chemoradiation after induction
ADVANTAGES & DISADVANTAGES OF DIFFERENT CHEMORADIATION
SEQUENCING
67. Platinum Compounds (Cisplatinum)
● MOA- Inhibition of DNA synthesis and transcription
-inhibition of repair of radiation induced DNA damage
● Cell cycle- nonspecific
● More toxic to hypoxic than aerated cells
● Also, radiation induces increased cellular cisplatin uptake
● Concurrent with radiation
Head & neck cancer(100mg/m2) three weekly regimen
Carcinoma cervix (40mg/m2) weekly regimen, lung cancer and esophageal cancer
Carboplatin
Dose- AUC-2 weekly regimen with paclitaxel in esophageal cancer and high risk
medulloblastoma
68. TOPOISOMERASE-1
INHIBITORS
■ Camptothecin (irinotecan, topotecan)
■ Inhibition of repair of radiation
induced DNA strand breaks
■ Redistribution into G-2 phase of the
cell
■ Conversion of radiation induces SSB
to DSB
■ Used in SCLC @ doses sequential-
200mg/m2 + cisplatin 80mg/m2
● Cell cycle – specific arrest in G2/M phase
which is highly radiosensitive
● Microtubule inhibitors
● Induction of apoptosis leads to
reoxygenation
● Used in esophageal cancer – paclitaxel
50mg/m2 weekly regimen with carboplatin
TAXANES
69. ANTIMETABOLITES (5-FLUROURACIL)
■ Incorporates into RNA disruption of RNA function
■ Inhibition of thymidylate synthetase function- inhibits DNA synthesis and results in
accumulation of cells in early phase
■ Direct incorporation of the drug into DNA
■ The combination of these effects underlie its radio-sensitizing effect
■ The combination of continuous infusion 5-FU and radiation is a mainstay of treatment
for GI tumors, anal cancer and bladder cancers
■ Also, along with RT in combination with Leucovorin weekly(375 mg/m2)
70. CAPECITABINE
■ Oral Fluoropyrimidine carbamate prodrug form of 5- fluorouracil
■ Antimetabolite and cytotoxic since thymidine phosphorylase is
overexpressed in tumor tissues
■ Capecitabine was shown to be safe to replace 5-FU in chemoradiotherapy
regimen for rectal cancer
■ Dose- 825 mg/m2 b.d.
■ Used in rectal cancer, esophageal cancer and gastric cancer
71. GEMCITABINE
■ Another nucleoside analog that
acts as a potent radiosensitizer
■ M.O.A- direct incorporation into
DNA and drug induced apoptosis
are underlie its cytotoxicity
■ S- phase specific and selective
toxic to proliferative cells
■ DOSE- 300-400mg/m2 weekly
in pancreatic cancer with RT
PEMETREXED
■ It is not cell cycle phase
specific,
■ Simultaneous inhibition of
multiple folate-requiring
enzymes including
thymidylate synthase
synergistic activity with
radiation seen because of
interference with DNA
synthesis
72. TEMOZOLAMID
E
● Alkylating agent
and cell cycle
nonspecific agent
● Metabolic
activation to the
VINCRISTINE
M-Phase specific drug
MOA- antitumor activity is due to primary to
inhibition of mitosis at metaphase through its
interaction with tubulin
Dose- 1.5 mg/m2 weekly regimen with
radiation in medulloblastoma
74. Activation leads to Enhancement of
proliferation ,tumor survival, and DNA
repair and further signalling is activated
after irradiation and has been
implicated in accelerated repopulation
EGFR blockade leads to reduction of
tumor cell repopulation by modulation
of cellular proliferation &
enhancement of tumor radio response
EGFR
pathways
75. CETUXIMAB
■ Specifically targets EGFR with high affinity and blocks ligand binding
■ Enhances antitumor activity of cisplatin / radiotherapy
■ Intravenous given one week before radiotherapy with loading dose of 400 mg per square
meter over a period of 120 mins f/b weekly 60 min infusion of 250mg/m2 for the duration of
radiotherapy
■ Side effects- angioedema , urticaria , hypotension , bronchospasm, Rash
■ Dose limiting side effect- Infusion related toxicity
Bonner et al showed treatment of locoregional H&N cancer with
concomitant high dose radiotherapy plus cetuximab improves
locoregional control and reduced mortality without increasing side
effects.
77. Protection Mitigation Treatment
measure applied before the
threshold dose for the
specific side effect is
reached
in the symptomatic phase to
reduce the side effects
Strategies used before the
manifestation of clinical
symptoms
78. IDEAL RADIOPROTECTOR
■ High therapeutic ratio
■ Easy and comfortable administration
■ Reasonable and cost-effectiveness
■ Should preserve of the anti-tumor efficacy of radiation
■ High efficacy /toxicity profile
80. HISTORICALLY
CYSTEINE
● a free SH group at one end
● strong basic function i.e., amine or guanidine at
other
■ Free radical scavenging
■ Hydrogen atom donation to facilitate direct
chemical repair at sites of DNA
■ The toxicity of the compound could be greatly
S-CH2-CHH
NH2
COOH
81. DOSE REDUCTION FACTOR
■ DRF- Dose of radiation in the presence of the drug/ dose of radiation in the
absence of the drug
■ Animals injected with cysteamine to concentrations of about 150mg/kg
require doses of x-rays 1.8 times larger than control animals to produce the
same mortality rate. This factor of 1.8 is called the DOSE REDUCTION
FACTOR, defined as to produce a given level of lethality
82. Two Radioprotectors in Practical Use
COMPOUND DOSE
(MG/KG)
DRF
7DAYS (GI)
DRF
30DAYS
(HEMATOP
OETIC)
USE
WR-638
CYSTAPHOS
500 1.6 2.1 Carried in field
pack by Russian
army
WR-2721
AMIFOSTINE
900 1.8 2.7 Protector in
radiotherapy and
carried by US on
lunar trips
83. AMIFOSTINE (WR-2721)
Walter Reed Army Research Institute, USA
AMIFOSTINE
( Phosphorothioate prodrug –inactive,
does not readily permeate cells)
ACTIVE THIOL
(WR 1065)
ENTER IN CELL BY FACILIATED
OXIDATION
DIFFUSION
WR- 33278 ( Polyamine like
disulphide metabolite)
84. WR-33278 ( ANTIMUTAGENIC)
A.RADIOPROTECTION B. ACCELERATED RECOVERY
1. Prevention of DNA damage a. upregulates the expression of proteins
➢ Condensation of DNA, thereby involved with DNA repair
limiting potential target sites b. Inhibits apoptosis, by Bcl-2 and
for free-radical attack hypoxia-inducible factor-1
➢ Anoxia c. Enhanced cellular proliferation
Rapid consumption of O2 levels
to induction of cellular anoxia
85. WHY SELECTIVE
CYTOPROTECTIO
N?
Extensive uptake is seen in:
1. Salivary glands
2. Kidneys
3. Intestinal mucosa
Markedly lower uptake is seen in
■ Tumor tissue
■ Amifostine and metabolites
do not cross the blood-brain
barrier
Differential expression of
alkaline phosphatase in tumor
tissue
Hypo vascularity & hypoxia
Low pH the tumor
100 folds decreased
concentration in
tumor tissue
86. ■ Not orally bioavailable
● Rapidly cleared from plasma; t1/2 < 1min and >90% drug cleared plasma 6 min
after administration
● Once Amifostine enters the plasma, it is rapidly metabolized and distributed in
tissues, whereas the excretion of the metabolic products is very low
■ Timely administration of amifostine is necessary
■ Amifostine before 30 min of RT provide optimal benefit for cytoprotection of
normal tissue.
■ Single morning dose of amifostine provides superior radioprotection than with a
single afternoon dose
87. ROUTES OF
ADMINISTRATION
■ At a dose of 200mg/m2 daily, given as a slow i.v. push over 3 mins,15-30 mins
before each fraction of radiation therapy after premedication
■ B.P. should be measured before and immediately after the 3 mins Amifostine
infusion
■ S/c injection of 500mg of amifostine
■ 1500 mg intra rectally 20-30 mins before each radiotherapy session Useful for
pelvic irradiation
■ Side effects : Nausea,Fever/rash reaction,Hypotension
88. SIDE EFFECTS
■ Nausea, vomiting & other GI effects
■ Transient hypotension-
■ Infusion related- flushing and feeling warmth, chills , dizziness,
somnolence, hiccups
& sneezing.
■ Hypocalcemia in <1%
■ Metallic taste during infusion
■ Allergic reactions include rash, fever and anaphylactic shock
89. GLUTAMINE
■ Glutamine is a neutral amino acid that acts as a substrate for nucleotide synthesis in most
dividing cells
■ It is the most abundant amino acid in free blood and constitutes 60% of the total free
amino acid pool in skeletal muscle
■ Glutamine metabolism regulated by glutaminase and glutamine synthetase which occur
primarily in skeletal muscle and brain.
■ States of physiologic stress, including those resulting from the treatment of malignant
disease , are characterized by a relative deficiency of glutamine
■ Supplementation with this inexpensive dietary supplement may have an important in
prevention GI, neurologic, and decreases mucosal membrane injury
90. MEMANTINE
■ NMDA receptor antagonist , open channel blocker that shown to be
neuroprotective and improve cognitive function in patients receiving WBRT
■ MOA- it binds to NMDA receptor and prevents the influx of calcium , thus
preventing the disruption of synaptic plasticity.
■ Dose-started within 3 days of initiation of WBRT and continued for 24 weeks
with gradual escalation from 5mg to 20 mg per day.
■ Side effects- fatigue, alopecia, nausea ,headache , dizziness, constipation
91. NITROXIDES
■ Are Antioxidants that convert between the
oxidized and reduced form
■ In, oxidized form, it exist as a stable free radical
that can undergo hydrogen reductions to
hydroxylamines
92. ■ Both are antioxidants functions, only nitroxides
RADIATION MITIGATORS
Alternatively, radiation mitigators can be delivered
during or shortly after exposure to repopulate a
critical cell compartment such as mucosa or bone
marrow
In this instance, the mitigator is used to prevent acute
toxicity
Radiation induce late normal toxicity
Events include mitotic cell death, active cytokines
cascades and extracellular matrix cell deposition
Mitigators aim to interrupt these cascades to prevent
the perpetuation of damage
Reduce the expression of toxicity
93. PALIFERMIN- Radiation Mitigator
■ Recombinant human keratinocyte growth (FIBROBLAST GROWTH
FACTOR 7)factor used to prevent and treat oral mucositis following
radiation or chemotherapy
■ Stimulates cell proliferation and differentiation in. mucosa of alimentary
tract, salivary glands, and type II pneumocytes
■ Enhances glutathione mediated cell protection too
■ Preclinical trials have shown requirement of increase in RT doses to cause
ulcerative mucositis
■ Predominant use till date has been for stem cell transplant with TBI
94. regimens before and after TBI at doses of 60mcg/Kg/day
CONCLUSION
■ Radiation as solo modality is not sufficient in majority of instances to cure cancers
mainly due to NTT
■ Cell hypoxia is one of the most correctable & exploited situation in clinic that has led to
important improvements in treatment outcomes
■ Newer molecular pathways are being studied for understanding mechanisms which can
increase radiosensitivity
■ Chemo-radiation continues to be the most significant radiosensitizer
■ Effective and feasible radiation protectors and mitigators have mostly been of
theoretical importance and their routine use in clinic is still a distant reality in day to day
practice
