Hypoxia in clinical radiotherapy and methods to overcome it

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TATA MEMORIAL HOSPITAL

HYPOXIA IN CLINICAL RADIOTHERAPY

& METHODS TO OVERCOME IT

Dr. Pramod Tike – JR I
Dr. Indranil Mallick – SR I
Monday, 2nd April 2007
DEPARTMENT OF RADIATION ONCOLOGY

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MECHANISM AND OXYGEN FIXATION HYPOTHESIS

• Absorption of radiation
• Fast charged particles produced
• Passing through biologic material
produce no. of ion pairs.
• Free radical production
• Breaks bonds
• Produce chemical changes
• This damage may be “fixed” by
Oxygen
-Hall, 1998


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THE IMPORTANCE OF OXYGEN

• “ The response of cells to ionization radiation is strongly
dependent upon Oxygen”1
• The enhancement of radiation damage by oxygen is dose modifying for
same level of biological damage.
• Oxygen Enhancement Ratio (OER) = Radiation damage in Hypoxia

Radiation dose in air

1.Grey et al 1953, Wright & Howard,Flanders 1957


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RADIATION DOSE MODYFYING EFFECT OF OXYGEN

10
Surviving fraction

1.0 Oxic
Hypoxic
0.10

0.01 OER=2.8

0.001

0 5 10 15 20 25 30 35
Radiation dose Gy
*with Xrays

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RADIATION DOSE MODYFYING EFFECT OF OXYGEN

10
Surviving fraction

1.0 Oxic
Hypoxic
0.10

0.01 OER=1.6
*with 15 mev neutrons (OER=1.6)
with α-rays (OER= 1.0)
0.001

0 5 10 15 20 25 30 35
Radiation dose Gy


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VARIATION IN OER WITH OXYGEN TENSION
O2
r
Ai 200 re
400 600 Pu 800
(curve B)

3
OER

2

Venous Arterial
1

0 10 20 30 40 50 60 70 80 90 100 (curve A)
Partial pressure of oxygen (mm Hg)


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TUMOR VASCULATURE


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Development of microscopic regions of necrosis in tumors

Stroma

Viable tumor

Necrosis

100 – 180 µm

Conclusions by Thomlinson and Gray from
studies on histological sections of human
bronchial carcinoma showing the development of
necrosis beyond a limiting distance from the
vascular stroma


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OXYGEN EFFECT
• Impact of oxygen diffusion on
radiation survival curve.


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TUMOR HYPOXIA

• Four different subpopulations of tumor cells with respect to
oxygenation.
– Well oxygenated viable & dividing
– Well oxygenated viable & non-dividing
– Poorly oxygenated viable & non-dividing
– Anoxic and/or necrotic non-viable


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TUMOR HYPOXIA

• There are two types of hypoxia
– Transient Hypoxia
• Intermittent in nature
• Can be quite severe
– Permanent Hypoxia
• Unrelieved hypoxia
• Severe to the point of causing cell death


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TUMOR HYPOXIA

• Intermittent Hypoxia
– Caused by vascular spasm
– Spasm usually at the arteriole level
– Due to lack or neurologic control of vessels
– May be mediated by vasopressors secreted by the tumor
– Increases radiation resistance
– Increase resistance to some drugs


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TUMOR HYPOXIA

• Permanent Hypoxia
– Occurs when tumor growth outstrips vascular supply
– Hypoxic cells are physically displaced from vessels.
– Oxygen diffusion distance varies with metabolism but beyond 100
microns hypoxia is probably profound.
– Tumor pressure on surrounding tissues may further impede blood
supply.


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REOXYGENATION

X-Rays
X-Rays
Aerated cells X-Rays
15% hypoxic cells

n
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tio

io

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at
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en
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yg

yg

en
x
eo
ox

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R Re

ox
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Mostly hypoxic cells

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REOXYGENATION

• Reoxygenation Fibrosarcoma
patterns observed in
preclinical tumor
Osteosarcoma
models treated with
radiation.
• Tannock and Hill,
1998.


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HYPOXIA IN CLINICAL PRACTICE


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UTERINE CERVIX

• Overall and disease-free
survival probabilities for
patients with advanced
cancers of the uterine cervix
treated with curative intent.
– Hoeckel et al, 1996


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Hb - HEAD & NECK CANCER

• Effect of hemoglobin level
on local – regional control
in Head and Neck Cancer.
• Overgaard et al, 1989


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Hb - HEAD & NECK CANCER

• Fein, D.A. et al - JCO 13:2077-2085, 1995
Local Control (%) Survival
Hb < 13 g/dL (%)
66
46
T1 - T2 Glottic Ca
p = .0018 p
N = 109 < .001

95
88
Hb > 13 g/dL


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BREAST

• Oxygen tensions (pO2 frequency
distributions) in normal breast and
breast cancers.
• Vaupel and Hoeckel, 1999


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SOFT TISSUE SARCOMA

• Soft tissue
sarcoma
survival as a
function of
tumor
oxygenation.
– Brizel, 1999


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HYPOXIA IN TUMORS

• Aggressiveness of Disease
– Hypoxia may provide a mutant p53 growth advantage (Graeber et al.,
1996).
– In carcinoma of the cervix, patients with hypoxic tumors treated with
surgery had a significantly worse disease-free and overall survival
compared to patients with non-hypoxic tumors (Hoeckel et al., 1996).


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• Overall and disease-free survival
probabilities in patients with advanced
cancers of the uterine cervix treated
with primary surgery.
• Hoeckel et al., 1996


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• Influence of tumor hypoxia on malignant progression.
-Giaccia et al., 1999


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HYPOXIA IN TUMORS

• Metastatic Spread
– Hypoxic exposure of tumor cells in vitro can increase metastases in mice
(Young et al., 1988).
– Increased metastases can occur in mice with primary hypoxic tumors
(De Jaeger et al., 2001).
– The probability of distant metastases in soft tissue sarcoma was twice as
great for tumors with median pO2 values < 10 mm Hg than for those with
median pO2 values > 10 mm Hg (Brizel et al., 1996).


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ANEMIA AND TUMOR HYPOXIA

• Hypoxic tumors are more likely to recur loco regionally than well oxygenated
tumors regardless of whether Sx or RT is primary local treatment.
– Hockel et al,Hypoxia and radiation response in in human tumors. Semin in rad onco 1996;6:3-9

• Hockel et al reported Higher 5 yr DFS in pts in which median oxygenation
measured with polarographic needles was atleast 10mmHg as compared to
pts. With Po2 <10mmHg.
• Higher incidence of pelvic rec. & lower survival rates in anemic pts treated
with RT
– Evans and Bergsjo et al(1965),Vigario et al(1973),
• Milosevic et al (IJROBP 1999;43:1111-1123) showed decrease in tumor
oxygenation related to increase in blood viscosity.


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ANEMIA AND TUMOR HYPOXIA

• Blood transfusions in pts with Hb < 10 g/dL showed significant improvement
in outcome ( Bush et al; Br J Canc1978;37:302-306)
• Threshold for transfusion based on anemia during treatment and not initial
Hb level ( Fyles et al; Radiother Oncol 2000;57:13-19)

Will BT to Hb levels above 12-12.5 g/dL improve prognosis??

• Retrospective reviev of 600 pts t/t for Ca Cx(Grogan et al:The importance of Hb
levels during RT for Ca Cx; cancer 1999;86:1528-1536)
Giving BT to maintaining avg. Hb level at that level during t/t is beneficial
regardless the Hb at presentation


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METHODS FOR MEASUREMENT OF TUMOR HYPOXIA

• Polarographic needles
• Eppendorf probes
• Molecular imaging


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HOW TO OVERCOME HYPOXIA ??


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HOW TO REDUCE HYPOXIA

• Fractionation
• Hyperbaric oxygen
• Hypoxic cell sensitizers
• Improving oxygenation of tumour
– Blood transfusion
– Perfluoro carbons
– Nicotinamide
– Carbogen+nicotinamide
– Angiotensin II
– Flunarizine


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HYPOXIC SENSITIZERS

• Misonidazole
• Etanidazole
• Pimanidazole
• RSU-1069
• Nimorazole (SER 1.3, +ve for head and neck and cervix)
• AK 2123
• Hyperthermia
• RSR 13 (Banoxantrone)*
• Motexafin Gadolinium*
• HIF-1 Inhibitor*
* Redox modulator in development, not approved by FDA yet


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HYPOXIC SENSITIZERS

Sensitizer Side Chain Advantages over misonidazole

SR 2508 CH2NHCOCH2CH2OH Decreased lipophilicity
Etanidazole Shorter half life
Lesser concn in brain
RO 03 8799 CH2CH(OH)CH2N More electron affinic and better sensitizer (x3)
Uncharged at acidic PH, and hence higher tumour
concentration (X 1.6)
RSU-1069 CH2CH(OH)CH2N Better sensitizer, bifunctional agent and hence highly
toxic to hypoxic cells less Neurotoxic but GI toxic

RO-07-0582 CH2CH(OH)CH2OCH3 Neurotoxic and hence cannot be used in
radiotherapy


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TO INCREASE HYPOXIA

• BW12C
• Hydralazine
• Photodynamic therapy to destroy blood vessels


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EFFECT OF FRACTIONATION

• administering smaller dose fractions
• oxygen effect is less profound at low doses. Thus hypoxic
tumour cells would be less radioresistant.
• If there is sufficient reoxygenation between fractions, a small
hypoxic tumour subpopulation would have less influence on
response to a sequence of small dose fractions as compared to
high dose fractions


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OXYGEN

• First radiation sensitizer used clinically
• Studies revealed the presence of necrotic zones in human
tumours and animal testing demonstrated that 1% to 50% of the
clonogenic cells in solid tumours could be radioresistant as a
result of hypoxia.


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HBOT

• Hyperbaric oxygen chambers were used to tackle the problem
of hypoxia.
• Infeasible because of cumbersome procedure, time involved
and fear of accident.
• Patient’s compliance
• Several clinical trial performed using oxygen as radiosensitiser
failed to show significant improvement in survival.


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BLOOD TRANSFUSIONS
• BT to maintaining higher Hb improves outcome
• Recombinant human erythropoietin (EPO): an alternative
means of raising Hb during radiotherapy
• Dose: 200 U/kg/day X 5 days/week expected to elevate Hb by
an average of 1-3 g/dL ( Dusenbery et al;IJROBP;1994:29, Lavey et
al;IJROBP;1993:27, Vijaykumar S;IJROBP;1993:26)

• Induces prompt reticulocyte response from 2.4% to 4.9%
• No proof that EPO is superior to BT with impact on clinical
outcome.
• Expensive than BT.


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NICOTINAMIDE AND CARBOGEN BREATHING

• To overcome the vasoconstriction caused by pure oxygen and
to improve the blood supply to tumour hence to reduce the
chronic hypoxia
• Nicotinamide, vit.B3 prevents transient fluctuation in tumour
blood flow hence reducing the acute hypoxia.


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ARCON

• Accelerated hyper fractionated radiation therapy while breathing carbogen
and with the addition of nicotinamide.
• Strategy was to accelerate treatment to avoid tumor proliferation, hyper
fractionate to minimize late effects and add carbogen breathing to overcome
chronic hypoxia and nicotinamide to overcome acute hypoxia.
• Early results of a trial of ARCON in Netherlands involving advanced
laryngeal cancers showed spectacular results.
• Results of a prospective randomized control trial are yet to be published.


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HYPOXIC RADIOSENSITIZERS

• Instead of forcing oxygen into hypoxic cells by use of high
pressure tanks, the approach shifted to oxygen substitutes
• These compounds get selectively activated in the hypoxic
environment of tumour cells


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CHARACTERISTICS OF HYPOXIC CELL SENSITIZERS

• Selective sensitivity to hypoxic cells at a concentration that
would result in acceptable toxicity to normal tissue.
• Chemical stability and not subject to rapid metabolic
breakdown.
• Must be highly soluble in water or lipid and must be capable of
diffusing considerable distance.
• It should be effective at relatively low daily doses of few grays .


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MISONIDAZOLE (LAB EXP.)

• Hypoxic cells in presence of
10nM of misinidazole have
radiosensitivity approaching
to that of aerated cells.


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MISONIDAZOLE CLINICAL-EXP

• 20 or so randomized prospective
controlled clinical trials failed to
show a statistically significant
advantage.
• Only trial which showed advantage
for Misonidazole was from
Denmark
• Dose limiting toxicities were
peripheral neuropathy that
progress to CNS toxicity if the drug
is not stopped.


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ETANIDAZOLE

• The compound equals to misonidazole as a sensitizer but is less toxic.
• Dose factor could be increased by 3.
• Shorter half life and lower partition coefficient so does not cross BBB.
• Controlled trial by RTOG in US and a multicenter consortium in Europe
showed no benefit from Etanidazole.


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NIMORAZOLE

• Less effective as a radiosensitiser but much less toxic
• Very large doses could be given
• In a Danish head and neck trial this compound showed a significant
improvement in both locoregional control and survival compared with
radiotherapy alone.


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• 422 patients were accrued
• Median time 112 months


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RESULTS

• Locoregional control was 49% v/s 33% p=0.002
• Same trend was also found in overall survival, but not to the
significant extent 26% v/s 16% p= 0.32
• Conclusion – Nimorazole significantly improves effect of
radiotherapy managemant of supraglotic and pharynx tumour
and can be given without major side effects


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n=61 pts , (StgIII=21, StgIV=40) of Advanced SCC H&N, Unsuitable for Sx
continuous hyperfractionated accelerated radiation therapy (CHART)+Nimorazole
RT=56.75 Gy/36#/12 consecutive days @ 157.64Gy/#
Nimorazole=orally or enterally 90 min before radiotherapy at a dose of 1.2, 0.9, and 0.6 g/m2
with the first, second and third daily fractions,respectively.
Loco-regional control at 2 years is 55%(StgIII=62%&StgIV=50%)
slight increase in acute skin reaction than previovs CHART
Nimorazole Toxicity was somewhat greater than those with once daily administration.
Grade 3 nausea/vomiting occurred in 22% of pts. 2 pts developed grade 1 peripheral neuropathy
1 pt. died during t/t of encephalopathy.


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RT= 62-68Gy/31-34#
@ 2Gy/# & 5#/week
Nimorazole= 1.2mg/m2 90 min before
RT during first 30#s
Placebo = Gelatine capsules


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AK-2123 (Sanazol)


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AK-2123 (Sanazol)
Local Tx control actuarial survival
at 60 months
RT+ AK2123
Initial n=462
4 centres excluded 61% 57%
n=333
7 pts did not undergo t/t
Finally (p = 0.006) (p = 0.01)
n=326 evaluated
46% 41%
Ca Cx IIIa+IIIb
RT Alone

RT= total dose of 45–50.8 Gy/20–28/4–5.5 weeks, with further dose escalation by
brachytherapy or external beam
AK-2123 = 0.6 g/m2 intravenous administration before external beam radiotherapy on
alternate days.

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HYPOXIC CYTOTOXINS

• Greater reductive environment of tumour might be exploited by developing
drug that are reduced preferentially to cytotoxic species in hypoxic regions
of tumour.


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HYPOXIC CYTOTOXINS

• Quinolone antibiotics
eg.Mitomycin C

• Nitroaromatic compounds

• Benzotriazine di-N-oxides
eg. Tirapazamine

• AQ4N*


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• Vienna HFA-RCT study showed
• Acturial overall survival 81% at one year,52%at two year and 33% at three year
• Locoregional controll-61%,55%,55%
• Radiation dose 64Gy (36Gy + 28Gy off cord)
• Mitomycin-C i.v. bolus over 10 min 20mg/m2 on day 5 of RT


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GERMAN ARO 95-6 TRIAL

4 YrSurvival (%) 4 Yr
dose escalated HFRT 77.6Gy LRC(%)
28
40
N = 373

34
HFRT 70.6Gy + concurrent Mitomycin-C 50

Both the arms were equal regarding the acute and late toxicities.


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Patients with advanced head and neck cancer were treated with
primary curative radiotherapy (66 Gy in 33fractions with five fractions
per week) ±a single injection (15 mg/m2) of MMC at the end of the
first week of radiotherapy.


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SCC of the oral cavity (n = 230), oropharynx(n = 140), hypopharynx (n = 65) or larynx (n = 43)

N=161N0
66Gy/33#/6.5weeks 3 Yr LRC (%) 3Yrs LRC(%)
18 16

N = 478
P=0.01
Stage III=223
Stage IV=255
21
29
66Gy/33#/6.5weeks + concurrent Mitomycin-C

Conclusions: The study did not show any major influence of MMC on loco-regional tumour
control, survival or morbidity after primary radiotherapy in stage III–IV head and neck cancer
except in N0 patients where loco-regional control was significantly improved.


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TIRAPAZAMINE

• TPZ is a benzotriazine compound that exhibits selective cytotoxicity for
hypoxic cells.
• Little clinical when used alone because the problem of nausea, vomiting,
diarrhea and sever muscle cramping.
• Various combinations studied
– Cisplat alone Vs Cisplat+TPZ :(CATAPULT I;2000)
– Cisplat+TPZ Vs cisplat+etoposide : (international phase III CATAPULT trial;2000)
– Cisplat+TPZ+Fluorouracil Vs cisplat+fluorouracil : (Pro Am Soc Clin Oncol
2002;21:227a)
– Cisplat+TPZ Vs cisplat+fluorouracil :(phase II trial TROG group;2005)
– Paclitaxel/Carboplat (PC) Vs PC+ Tirapazamine (PCT): (phase III SWOG
trial;2003)


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• Initial phase III study(n= 440) with advanced NSCLC treated with cisplatin alone
Vs Cisplat+TPZ (CATAPULT I) showed positive results:
Cisplat (75mg/m2) Vs Cisplat (75mg/m2)+TPZ(390mg/m2)

Response rate 14% 27.5%
Overall survival 8 months 6 months
1 Yr survival 33% 22%
• Unfortunately, the follow-up study [CATAPULT II]failed to demonstrate similar
survival advantages
TPZ (390 mg/m2) + cisplatin (75mg/m2) Vs etoposide (100 mg/m2) plus cisplatin (75 mg/m2).
The TPZ-containing arm proved to be more toxic and less
effective.
•third phase III trial :TPZ ± paclitaxel/carboplatin in patients with advanced NSCLC.
(SWOG0003)
PC Vs PC+TPZ
Overall survival 8 months 11 months (37% improvement)
did not result in improved response, time to progression

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TIRAPAZAMINE


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HYPERTHERMIA

• Mild hyperthermia can improve the tumour reoxygenation, with
the degree of reoxygenation correlating with the level of
cytotoxicity.
• In addition to antitumour effect of heat, it has synergistic effect
with radiation


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MOLECULAR PROFILING


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BIOLOGICAL TARGET VOLUME/ BIOLOGICAL EYE VIEW
Biological tumor volume – Derived from biological images and their use may guide
customized dose delivery to various parts of treatment volume.


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Thank You!


Hypoxia in clinical radiotherapy and methods to overcome it

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