Hypoxia PKTK

TMH TATA MEMORIAL HOSPITAL
HYPOXIA IN CLINICAL RADIOTHERAPY & METHODS TO OVERCOME IT
Monday, 2nd April 2007
Dr. Pramod Tike JR I Dr. Indranil Mallick SR I

DEPARTMENT OF RADIATION ONCOLOGY

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

THE IMPORTANCE OF OXYGEN
The response of cells to ionization radiation is strongly dependent upon Oxygen1

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

RADIATION DOSE MODYFYING EFFECT OF OXYGEN
10
Surviving fraction
1.0
Oxic Hypoxic
0.10
0.01
OER=2.8
0.001
10 15
20 25
30
35
Radiation dose Gy
*with Xrays

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 -rays (OER= 1.0) 30 35
0.001
10 15
20 25
Radiation dose Gy

VARIATION IN OER WITH OXYGEN TENSION
200 400 600 800
(curve B)
OER
2 Venous 1 Arterial
10
20
Partial pressure of oxygen (mm Hg)
30
40
50
60
70
80
90 100 (curve A)

TUMOR VASCULATURE

Development of microscopic regions of necrosis in tumors
Stroma Viable tumor Necrosis
100 180 m
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

OXYGEN EFFECT
Impact of oxygen diffusion on radiation survival curve.
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
TMH TATA MEMORIAL HOSPITAL 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
TMH TATA MEMORIAL HOSPITAL 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
TMH TATA MEMORIAL HOSPITAL 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.

REOXYGENATION
X-Rays
X-Rays
Aerated cells 15% hypoxic cells
X-Rays
Etc.
Mostly hypoxic cells

REOXYGENATION
Reoxygenation patterns observed in preclinical tumor models treated with radiation. Tannock and Hill, 1998.
Fibrosarcoma
Osteosarcoma
HYPOXIA IN CLINICAL PRACTICE

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

Hb - HEAD & NECK CANCER
Effect of hemoglobin level on local regional control in Head and Neck Cancer. Overgaard et al, 1989

Hb - HEAD & NECK CANCER
Fein, D.A. et al - JCO 13:2077-2085, 1995
Local Control (%)
Hb < 13 g/dL 66 T1 - T2 Glottic Ca N = 109 95 Hb > 13 g/dL 88 p = .0018 46 p < .001
Survival (%)
TMH TATA MEMORIAL HOSPITAL BREAST

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

SOFT TISSUE SARCOMA
Soft tissue sarcoma survival as a function of tumor oxygenation.
Brizel, 1999
TMH TATA MEMORIAL HOSPITAL 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).
Overall and disease-free survival probabilities in patients with advanced cancers of the uterine cervix treated with primary surgery. Hoeckel et al., 1996

Influence of tumor hypoxia on malignant progression. -Giaccia et al., 1999
TMH TATA MEMORIAL HOSPITAL 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).

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.

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

METHODS FOR MEASUREMENT OF TUMOR HYPOXIA
Polarographic needles Eppendorf probes Molecular imaging
HOW TO OVERCOME HYPOXIA ??

HOW TO REDUCE HYPOXIA
Fractionation Hyperbaric oxygen Hypoxic cell sensitizers Improving oxygenation of tumour
Blood transfusion Perfluoro carbons Nicotinamide Carbogen+nicotinamide Angiotensin II Flunarizine

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

HYPOXIC SENSITIZERS
Sensitizer Side Chain Advantages over misonidazole
SR 2508 Etanidazole
CH2NHCOCH2CH2OH
Decreased lipophilicity Shorter half life Lesser concn in brain More electron affinic and better sensitizer (x3) Uncharged at acidic PH, and hence higher tumour concentration (X 1.6) Better sensitizer, bifunctional agent and hence highly toxic to hypoxic cells less Neurotoxic but GI toxic
RO 03 8799
CH2CH(OH)CH2N
RSU-1069
CH2CH(OH)CH2N
RO-07-0582
CH2CH(OH)CH2OCH3
Neurotoxic and radiotherapy
hence
cannot
be
used
in

TO INCREASE HYPOXIA
BW12C Hydralazine Photodynamic therapy to destroy blood vessels

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

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.

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

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.

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.

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.

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
TMH TATA MEMORIAL HOSPITAL 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 .
TMH TATA MEMORIAL HOSPITAL MISONIDAZOLE (LAB EXP.) Hypoxic cells in presence of 10nM of misinidazole have radiosensitivity approaching to that of aerated cells.
TMH TATA MEMORIAL HOSPITAL 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.
TMH TATA MEMORIAL HOSPITAL 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.
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.

422 patients were accrued Median time 112 months

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

AK-2123 (Sanazol)

AK-2123 (Sanazol)
Initial n=462 4 centres excluded n=333 7 pts did not undergo t/t Finally n=326 evaluated Ca Cx IIIa+IIIb RT+ AK2123
Local Tx control
actuarial survival at 60 months
61%
(p = 0.006)
57%
(p = 0.01)
46%
RT Alone
41%
RT= total dose of 4550.8 Gy/2028/45.5 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.
TMH TATA MEMORIAL HOSPITAL 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.
TMH TATA MEMORIAL HOSPITAL HYPOXIC CYTOTOXINS

Quinolone antibiotics eg.Mitomycin C Nitroaromatic compounds
Benzotriazine di-N-oxides eg. Tirapazamine

AQ4N*
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 DEPARTMENT OF RADIATION ONCOLOGY
TMH TATA MEMORIAL HOSPITAL GERMAN ARO 95-6 TRIAL
4 YrSurvival (%)
dose escalated HFRT 77.6Gy
4 Yr LRC(%)
28
N = 373
40
34
HFRT 70.6Gy + concurrent Mitomycin-C
50
Both the arms were equal regarding the acute and late toxicities. DEPARTMENT OF RADIATION ONCOLOGY
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.

SCC of the oral cavity (n = 230), oropharynx(n = 140), hypopharynx (n = 65) or larynx (n = 43)
66Gy/33#/6.5weeks
3 Yr LRC (%)
3Yrs LRC(%)
N=161N0
16
P=0.01
18
N = 478
Stage III=223
Stage IV=255
21
66Gy/33#/6.5weeks + concurrent Mitomycin-C
29
Conclusions: The study did not show any major influence of MMC on loco-regional tumour control, survival or morbidity after primary radiotherapy in stage IIIIV head and neck cancer except in N0 patients where loco-regional control was significantly improved. DEPARTMENT OF RADIATION ONCOLOGY
TMH TATA MEMORIAL HOSPITAL 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)

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 Overall survival 1 Yr survival 14% 8 months 33% 27.5% 6 months 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
TMH TATA MEMORIAL HOSPITAL TIRAPAZAMINE

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
MOLECULAR PROFILING

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.
Thank You!

Hypoxia PKTK

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TMH TATA MEMORIAL HOSPITAL

HYPOXIA IN CLINICAL RADIOTHERAPY & METHODS TO OVERCOME IT

Monday, 2nd April 2007

Dr. Pramod Tike JR I Dr. Indranil Mallick SR I

TMH TATA MEMORIAL HOSPITAL

DEPARTMENT OF RADIATION ONCOLOGY

TMH TATA MEMORIAL HOSPITAL

The response of cells to ionization radiation is strongly dependent upon Oxygen1

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

DEPARTMENT OF RADIATION ONCOLOGY

TMH TATA MEMORIAL HOSPITAL

DEPARTMENT OF RADIATION ONCOLOGY

TMH TATA MEMORIAL HOSPITAL

*with 15 mev neutrons (OER=1.6) with -rays (OER= 1.0) 30 35

TMH TATA MEMORIAL HOSPITAL

Partial pressure of oxygen (mm Hg)

DEPARTMENT OF RADIATION ONCOLOGY

TMH TATA MEMORIAL HOSPITAL

DEPARTMENT OF RADIATION ONCOLOGY

TMH TATA MEMORIAL HOSPITAL

Stroma Viable tumor Necrosis

DEPARTMENT OF RADIATION ONCOLOGY

TMH TATA MEMORIAL HOSPITAL

DEPARTMENT OF RADIATION ONCOLOGY

TMH TATA MEMORIAL HOSPITAL

Poorly oxygenated viable & non-dividing

DEPARTMENT OF RADIATION ONCOLOGY

DEPARTMENT OF RADIATION ONCOLOGY

TMH TATA MEMORIAL HOSPITAL TUMOR HYPOXIA Intermittent Hypoxia

May be mediated by vasopressors secreted by the tumor

DEPARTMENT OF RADIATION ONCOLOGY

TMH TATA MEMORIAL HOSPITAL TUMOR HYPOXIA Permanent Hypoxia

microns hypoxia is probably profound.

DEPARTMENT OF RADIATION ONCOLOGY

TMH TATA MEMORIAL HOSPITAL

Aerated cells 15% hypoxic cells

Mostly hypoxic cells

DEPARTMENT OF RADIATION ONCOLOGY

TMH TATA MEMORIAL HOSPITAL

DEPARTMENT OF RADIATION ONCOLOGY

TMH TATA MEMORIAL HOSPITAL

HYPOXIA IN CLINICAL PRACTICE

DEPARTMENT OF RADIATION ONCOLOGY

TMH TATA MEMORIAL HOSPITAL

DEPARTMENT OF RADIATION ONCOLOGY

TMH TATA MEMORIAL HOSPITAL

DEPARTMENT OF RADIATION ONCOLOGY

TMH TATA MEMORIAL HOSPITAL

DEPARTMENT OF RADIATION ONCOLOGY

TMH TATA MEMORIAL HOSPITAL BREAST

DEPARTMENT OF RADIATION ONCOLOGY

TMH TATA MEMORIAL HOSPITAL

DEPARTMENT OF RADIATION ONCOLOGY

TMH TATA MEMORIAL HOSPITAL HYPOXIA IN TUMORS Aggressiveness of Disease

surgery had a significantly worse disease-free and overall survival

DEPARTMENT OF RADIATION ONCOLOGY

TMH TATA MEMORIAL HOSPITAL

DEPARTMENT OF RADIATION ONCOLOGY

TMH TATA MEMORIAL HOSPITAL

DEPARTMENT OF RADIATION ONCOLOGY

TMH TATA MEMORIAL HOSPITAL HYPOXIA IN TUMORS Metastatic Spread

DEPARTMENT OF RADIATION ONCOLOGY