Demo slides

1
Oxygen and radiotherapy (Tumor hypoxia imaging
and radiotherapy)
W. De Neve
Ghent University Hospital
2

• Oxygen and radiation sensitivity (B. Thierens)
• Hypoxia in tumors (B. Thierens)
• Hypoxia and (radio)therapeutic outcome
• Hypoxia-directed therapies and radiotherapy
• Anemia and (radio)therapeutic outcome
• Hypoxia imaging and physical targeting

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Hypoxia and (radio)therapeutic outcome
Tumor sites Cervix, head and neck, prostate,
brain, sarcoma Type of study Case
series Methods Eppendorf Endpoints pO2 2.5, 5,
10 mm Hg, median, Hypoxic subvolume Local
control, survival, metastasis Statistics Uni- and
multivariate
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(1) Results of RTCT in head and neck
cancer related to intratumor O2 tension
1st Author Rudat (1) Stadler (2)
Treatment HART 69.9 Gy carbo-5FU 66-72 Gy
or HART 77.6 Gy MMC-5FU
Key findings 3-y S higher (p 0.05) in patients
with HF ? 26.8 versus gt26.8 (median) HF and
HSV prognostic for S (p lt 0.05)
Stage (n) IVA (41) IVA (59)
HF hypoxic fraction pO2 values ? 2.5 mm
Hg HSV hypoxic subvolume HF x tumor volume S
actuarial survival

• Radiother Oncol 2000573137
• Int J Radiat Oncol Biol Phys 199944749754

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(2) Results of RTCT in head and neck
cancer related to intratumor O2 tension
1st Author Brizel (3) Nordsmark (4)
Treatment 66-72 Gy Surg HART 75 Gy HART
cis-5FU 66-68 Gy or 54 Gy in 18 F nimorazole
Key findings Median pO2 gt10 mm Hg Higher S, DFS
and LC local control (p lt 0.02) 2-y LC 33 vs
77 (p 0.01) with median HF gt15 vs ? 15
Stage (n) ? IVA (63) ? IVA (35)
HF hypoxic fraction pO2 values ? 2.5 mm Hg S
actuarial survival DFS disease free survival
LC local control
(3) Radiother Oncol 199953113117 (4) Radiother
Oncol 1996413139
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(1) Results of RTCT in cervix cancer related to
intratumor O2 tension
1st Author Rofstad (1) Knocke (2)
Treatment 50 Gy brachy 29-34 Gy 26-50.6Gy
brachy 21-25 Gy
Key findings HSV prognostic for LC (p 0.006),
DFS (p lt0.0001) and S (p 0.001) 3-y DFS 66
and 36 with HF lt 22 and ? 22 (p lt0.02)

• Stage (n)
• IB-IVA (32)
• Para-aortic
• N (51)

HF hypoxic fraction pO2 values ? 5.0 mm
Hg HSV hypoxic subvolume HF x tumor volume S
actuarial survival DFS disease free survival
LC local control
(1) Br J Cancer 200083354359 (2) Radiother
Oncol 19995399104
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(2) Results of RTCT in cervix cancer related to
intratumor O2 tension
1st Author Fyles (3) Höckel (4)
Treatment 45-50 Gy brachy 40 Gy ? 45 Gy
brachy 24-28 Gy ev. other
Key findings 2-y DFS 69 and 34 with HF ? 50
and gt 50 (p 0.02) S, DFS higher (p
0.0085) if median pO2 ? 10 mm Hg Median pO2
strongest indep. prognostic factor for S, DFS

• Stage (n)
• IB-IIIB (74)
• IB-IVB (89)

HF hypoxic fraction pO2 values ? 5.0 mm Hg S
actuarial survival DFS disease free survival
(3) Radiother Oncol 199848149156 (4) Cancer
Res 19965645094515
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Hypoxia-directed therapies and radiotherapy
Hyperbaric oxygen Hypoxic cell sensitizers Carboge
n Nicotinamide (vascular agents)
Results considered below expectations
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Hypoxic cell sensitizers
Nine different drugs (misonidazole,
metronidazole, benznidazole, desmethylmisonidazole
, etanidazole, pimonidazole, nimorazole,
ornidazole, and RSU 1069) have reached clinical
evaluation. More than 7000 patients have been
included in 50 randomized trials. A
meta-analysis showed that modification of tumor
hypoxia significantly improved the loco-regional
tumor control after radiotherapy with an odds
ratio of 1.17 (95 confidence limits 1.06 to
1.28). The overall survival rate was
improved with an odds ratio of 1.13 (95
confidence limits 1.03 to 1.23) The median
number of patients per trial was only 97 (range
17-620). Clinical trials of this size are not
likely to detect the observed differences, which
may explain the lack of significant
improvement in most of the individual studies.
Overgaard Oncol Res. 19946(10-11)509-18
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Tumor hypoxia negatively affects prognosis
and decreases radiocurability of solid tumors
such as head and neck, cervical, prostate and
other.
Hypoxia-directed treatments cannot fully reverse
these effects of tumor hypoxia. Why?
Hypoxia is shown to be directly or indirectly
mutagenic, with selection of cells deficient in
p53-mediated apoptosis, mismatch repair, ..
Therefore, interventions that simply
improve intratumoral oxygenation would be
unlikely to reverse completely the negative
prognostic impact of hypoxia. This may explain
the generally limited benefit obtained by
hyperbaric oxygen, carbogen breathing, hypoxic
sensitisers
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Anemia and (radio)therapeutic outcome
Tumor sites Cervix, head and neck, brain,
sarcoma Type of study Case series Methods Blood
hemoglobin levels Endpoints Hb (g/dl) infra-,
normo and supra-physiologic levels local
control, survival, metastasis Statistics Uni- and
multivariate
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(1) Results of RTCT in cervix cancer related to
pretreatment hemoglobin levels
1st Author Hong (1) Kagei (2) Kapp (3) Mundt
(4)

• Hb g/dl
• lt 10
• ?10.8
• 11.0
• 11.0

Key findings 5-y DSS (p 0.009) 5-y DSS (p
0.0015) 5-y DSS (p 0.0015) 5-y LC (p
0.0004) Risk of M (p 0.027) 8-y DSS (p lt
0.0001)

• FIGO (n)
• I-IVA (401)
• II-III (217)
• IB-IV (181)
• IB-IVA (410)

S actuarial survival DFS disease free S DSS
disease specific S LC local control
(1) Int J Radiat Oncol Biol Phys
199841823830 (2) Radiother Oncol
199847207213 (3) Int J Radiat Oncol Biol Phys
199842531540 (4) Gynecol Oncol 199871151158
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(2) Results of RTCT in cervix cancer related to
pretreatment hemoglobin levels
1st Author Takeshi (5) Pedersen (6)
Hb g/dl Continuous Continuous
Key findings 5-y S (p 0.006) 5-y DFS (p
0.011) 5-y LC (p 0.07) 5-y S (p 0.008) 5-y
LC (p 0.01) 5-y MFS (p lt 0.003)
FIGO (n) III (265) IIB-IVA (424)
S actuarial survival DFS disease free S MFS
metastasis free S LC local control
(5) Int J Radiat Oncol Biol Phys
199841319327 (6) Acta Oncol 199534787795
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(1) Results of RTCT in head and neck
cancer related to pretreatment hemoglobin levels
1st Author Stadler (1) Grant (2) Lee (3)
Hb g/dl ? 12.5 lt 13.0 lt 11.5 lt 14.5 lt 13.0
Key findings S (p 0.01) DFS (p
0.0094) 5-y LC (p 0.0032) 5-y S (p lt 0.009)
Stage (n) ? IVA (59) larynx T1-T2 (117) III-IV
(451)
S actuarial survival DFS disease free S LC
local control
(1) Int J Radiat Oncol Biol Phys
199944749754 (2) J Laryngol Otol
1999113829833 (3) Int J Radiat Oncol Biol Phys
19984210691075
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(2) Results of RTCT in head and neck
cancer related to pretreatment hemoglobin levels
1st Author Warde (4) Dubray (5) Fein (6)
Hb g/dl Continuous lt 13.5 lt 12.0 Continuous
Key findings LC (p 0.006) 2-y LC (p
0.06) 2-y LC (p 0.0016) 2-y S (p lt 0.0001)
Stage (n) Glottic T1-T2 (735) M0
(217) Glottic T1-T2 (109)
S actuarial survival LC local control
(4) Int J Radiat Oncol Biol Phys
199841347353 (5) Radiology 1996201553558 (6)
J Clin Oncol 19951320772083
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Partitioning of patients according to
preradiation hemoglobin levels, even when within
the range of 12-14 g/dl, allows to define
groups with substantial difference in
locoregional control and survival. A direct
association between anemia and tumor hypoxia
appears likely, but it needs to be
confirmed. Transfusions and/or r-HuEPO are able
to correct anemia but it needs to be demonstrated
that these interventions have a substantial
prognostic impact.
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Hypoxia imaging and physical targeting
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Two hypoxic patients Note the total absence of
well-oxygenated regions
Movsas et al. 2002, J. Urology
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Two aerobic patients Note the absence of
hypoxic regions
Movsas et al. 2002, J. Urology
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Hypoxia-image guided dose escalation
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Conclusions

• Hypoxia imaging in oncology
• determine prognosis
• guide choice of treatment
• select and monitor patients for trials using
• hypoxia-directed strategies
• bifunctional drugs
• high-LET radiation
• topographical map for focused dose escalation

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Kraemer, Jaekel et al From ion tracks to ion
radiotherapy Lisbon workshop, June 2002.
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From Barendsen 1968
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(No Transcript)
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Joiner M C (2002) Particle beams in radiotherapy.
In Basic Clinical Radiobiology 3rd Edition (GG
Steel Ed.) London Arnold.
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(No Transcript)
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(No Transcript)
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Joiner M C (2002) Particle beams in radiotherapy.
In Basic Clinical Radiobiology 3rd Edition (GG
Steel Ed.) London Arnold.
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LOCAL-CONTROL PREDICTIONS (2-Gy
fractions) Prostate data Nahum 2003
Aerobic Hypoxic
Non-zero sa
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The Oxygen effect revisited For neutrons
OER seems close to unity For light ions in the
SOBP, the OER seems to be close to 2 For low LET
qualities, at relevant fraction sizes of 2 Gray,
the OER is also close to 2. CONCLUSION NO
SIGNFICANT ADVANTAGE EXPECTED FOR LIGHT IONS OVER
2-GY FRACTIONATED LOW-LET TREATMENTS
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Are there other important factors in prostate
tumours? YES clear evidence of hypoxia Movsas,
Chapman, Horwitz et al (2002) Eppendorf probe
measurements on hundreds of LDR brachy
seed-implant patients CORRELATION BETWEEN
FAILURE and high levels of HYPOXIA low
p-value
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PARAMETERS DERIVED DIRECTLY FROM RADIOBIOLOGY
Intrinsic radiosensitivity a 0.260 sa
0.06 b 0.0312 Oxygen Effect
OERa 1.75 OERb
3.25 Clonogen number N 5 x
106 Dose fraction size d 2 Gy
OERa 1.75 OERb 3.25
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LOCAL-CONTROL PREDICTIONS (2-Gy fractions) Our
radiosensitivity values Aerobic
Hypoxic
Non-zero sa
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PSA lt 10 ng/ml
100 AEROBIC 106 clonogens
PSA 10-20 ng/ml
100 HYPOXIC 107 clonogens
PSA gt 20 ng/ml