Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3618_Библиотеки_им_академика_М_И_Перельмана
.pdf
162 Radiation safety concerns associated with preparing the dosage, treating and releasing the patient
absorbed dose, and the dierence between the estimated absorbed dose delivered and the prescribed
absorbed dose exceeded the threshold for reporting a misadministration (0.5 Sv equivalent dose to
an organ or tissue). us, reporting this medical
event to the NRC or Agreement State regulatory
authority was required.
7.7.3 STORAGE FOR DECAY AND
DISPOSAL
e radioactive waste from each radioembolization procedure requiring a period of decay-instorage prior to disposal typically consists of (1)
one or more waste jars containing the residual
infusion system activity (sealed and removed
from the reusable acrylic shield); (2) any biohazard bags containing microspheres-contaminated
items such as gloves, garments, surface coverings,
and absorbent media employed in the removal of
microspheres from contaminated surfaces; and
(3) any unused treatment doses due to procedure
cancellation or an emergent patient condition.
Each of these sources of radioactive waste must
be appropriately labeled. e label for each should
include
1. R adionuclide (90Y)
2. Product (SIR-Sphere or eraSphere)
3. Date and time
4. Activity (mCi or GBq) for each residual activity
waste jar (Figure 7.17) and unused dosage
e 90Y in SIR-Spheres is eluted from a 90Sr/90Y
generator and thus there would ideally be no
radionuclidic impurities in the radioactive waste.
However, trace amounts of 90Sr have been detected
in SIR-Spheres waste due to “breakthrough” during the elution process, with amounts of 90Sr on
the order of 3 Bq per GBq of 90Y at the time of
manufacturer assay reported (Metyko et al., 2014).
As a consequence, SIR-Spheres waste will remain
slightly radioactive with both 90Sr and the 90Y it
is generating (both decaying with the 28.79 year
half-life of 90Sr) aer all of the initial 90Y activity
has essentially decayed away (Figure 7.18). On the
other hand, the negligible amount of 90Sr impurity
suggests that the duration of time over which the
radiation level external to the source container is
distinguishable from background before it may be
disposed of as regular, biohazard waste may not
Figure 7.17 Example 90Y microspheres residual
waste jar, labeled for decay-in-storage and later
disposal.
be signicantly aected. (Of course, the eect will
depend on the geometry and self-shielding of the
container and its contents, and the distribution of
microspheres within, in addition to the amount of
90
Sr impurity.)
Yttrium-90 is activated in eraSphere
microspheres by neutron bombardment. e
microspheres are manufactured with 89Y as a
constituent of the glass matrix, and 90Y is produced via the irradiation of the microspheres
in a nuclear reactor (89Y(n,γ)90Y). eraSphere
microspheres are known to contain a number
of gamma-emitting radionuclidic impurities as
a result of neutron activation of other elements
within the glass matrix (NRC, 2007; Ostrowski
et al., 2007; Nelson et al., 2008; Metyko et al.,
2012). e impurities that have been detected
have much longer half-lives than that of 90Y. e
two most prominent impurities are 88Y (106.6-day
half-life) and 91Y (58.5-day half-life) due to the
References 163
(b)
# β particles per nuclear transition
-90
(a)
Counts
Energy (KeV)
2500
Figure 7.18 Strontium-90 impurity in SIR-Spheres. (a) Theoretical β energy spectrum for 90Sr/90Y.
(b) Liquid scintillation counter β energy spectrum of an aliquot from an unused SIR-Spheres v-vial,
long after the original 90Y radioactivity had decayed to the level of background, demonstrating the
production of 90Y from the decay of on-board 90Sr.
Figure 7.19 Radionuclidic impurities in
TheraSphere. A high-purity germanium detector,
high-resolution γ-ray emission spectrum from
an unused TheraSphere v-vial, long after the
original 90Y radioactivity had decayed to the level
of background. A number of γ-emitting impurities were present, most notably 88Y (898 keV and
1.836 MeV).
reactions 89Y(n,2n)88Y and 89Y(2n,γ)
tively (Figure 7.19). Both produce high-energy
gamma emissions as a result of radioactive decay
and two from 88Y are high yield (898 keV/93.4%,
1.836 MeV/99.4%). Depending upon an institution’s RAM license and local regulations and
whether or not the radioactive impurities in
the procedure waste are detectable above background, the radioactive waste from eraSphere
procedures may have to be shipped to an outside
entity for decay-in-storage and disposal.
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00
4000000
3500000
3000000
2500000
2000000
1500000
1000000
500000
eoretical 90Sr/90Y spectrum
0 500 1500 2000 2500
0
1000
Energy (KeV)
250 500 750
1000
1250
1500
Total
Y-90
Sr
1750 2000 2250
91
Y, respec-
Counts #
1200
1000
800
600
400
200
0
0400 800 1200
1600 2000 2400
KeV
7.8 CONCLUSIONS
Radioembolization is a unique therapeutic application of RAM and as a consequence presents correspondingly unique challenges from a radiation
safety perspective. e intent of this chapter is to
arm the radioembolization team (interventional
radiologists, medical physicists, nuclear medicine
physicians, and/or radiation oncologists) with a
thorough understanding of the dosage preparation, patient treatment and release, and radioactive
waste management radiation concerns specic to
both SIR-Spheres and eraSphere. All members
of the interdisciplinary radioembolization team
should be keenly aware of and adhere strictly to
the various regulatory and good radiation safety
practice aspects associated with this treatment
modality. Doing so will help ensure that a licensee
establishes and maintains a radioembolization
program that is both safe and eective for patients,
while simultaneously safeguarding personnel and
members of the public against excessive radiation
exposure.
REFERENCES
Berger, M.J. (1976). MIRD Pamphlet 7:
Distribution of Absorbed Dose Around Point
Sources of Electrons and Beta Particles in
Water and Other Media. Reston, VA: The
Society of Nuclear Medicine and Molecular
Imaging.
164 Radiation safety concerns associated with preparing the dosage, treating and releasing the patient
Braat, A.J.A.T. et al. (2015). 90Y hepatic radio-
embolization: An update on current practice and recent developments. J Nucl Med
56:1079–1087.
BTG International Ltd. (2010). TheraSphere®
Reference Manual [Accessed February 24, 2011].
BTG International Ltd. (2014). Package Insert –
TheraSphere® Yttrium-90 Glass Microspheres.
Available from: http://www.therasphere.com/
physicians-package-insert/TS_PackageInsert_
USA_v12.pdf [Accessed August, 2015].
Busse, N., Erwin, W., Pan, T. (2013). Evaluation
of a semiautomated lung mass calculation
technique for internal dosimetry applications.
Med Phys, 40:122503.
Carey, J.E. et al. (2012). AAPM report no. 181:
The selection, use, calibration, and quality
assurance of radionuclide calibrators used in
nuclear medicine. American Association of
Physicists in Medicine, One Physics Ellipse,
College Park, MD, 20740-3846.
Cole, A. (1969). Absorption of 20-eV to 50,000 eV
electron beams in air and plastic. Radiat Res
38:7–33.
Dezarn, W.A. et al. (2011). Recommendations of the
American Association of Physicists in Medicine
on dosimetry, imaging, and quality assurance
procedures for
90
Y microsphere brachytherapy
in the treatment of hepatic malignancies. Med
Phys 38:4824–4845. Available from: http://www.
aapm.org/pubs/reports/RPT_144.pdf [Accessed
October 17, 2011].
Dieudonné, A. et al. (2011). Clinical feasibility of
fast 3-dimentional dosimetry of the liver for
treatment planning of hepatocellular carcinoma. J Nucl Med 52:1930–1937.
Eckerman, K.F., Endo, A. (2008). MIRD:
Radionuclide Data and Decay Schemes,Second
Edition. Reston, VA: The Society of Nuclear
Medicine and Molecular Imaging.
Emami,B. et al. (1991). Tolerance of normal tissue
to therapeutic irradiation. Int J Radiat Oncol
Biol Phys 21:109–122.
Erwin, W. et al. (2012). A measured bremsstrah-
lung dose rate constant for yttrium-90 microsphere liver directed brachytherapy. J Nucl
Med 53(Suppl 1):2230.
Erwin, W. (2012). Accuracy of yttrium-90 micro-
spheres delivery vial exposure rate measurement: Effect on estimated percent of activity
delivered. J Nucl Med 53(Suppl 1):2244.
Ford, K. (1955). Predicted 0
+
level of Zr90. Phys
Rev 98:1516.
Gress, D., Erwin, W. (2015). SIR-Spheres dose vial
activity assay cross-calibration with an outside
radiopharmacy. Med Phys 42:3498.
Gulec, S.A., Siegel, J.A. (2007). Posttherapy
radiation safety considerations in radiomicrosphere treatment with
90
Y-microspheres. J
Nucl Med 48:2080–2086.
Ho, S. et al. (1996). Partition model for estimating
radiation doses from yttrium-90 microspheres
in treating hepatic tumours. Eur J Nucl Med
23:947–952.
Harding, L.K. et al. (2004). ICRP publication
94: Release of patients after therapy with
unsealed radionuclides. Ann ICRP 34:1–80.
ICRU. (1984). Report 37: Stopping Power for
Electrons and Positrons. Bethesda, MD:
International Commission on Radiation Units
and Measurements.
Johnson, O., Johnson, R., Langer, L. (1955).
Evidence for a 0
+
rst excited state in Zr90.
Phys Rev 98:1517–1518.
Kao, Y.H. et al. (2012). Image-guided personal-
ized predictive dosimetry by artery-specic
SPECT/CT partition modeling for safe and
effective
90
Y radioembolization. J Nucl Med
53:559–566.
Kennedy, A. et al. (2007). Recommendations for
radioembolization of hepatic malignancies
using yttrium-90 microsphere brachytherapy:
A consensus panel report from the radioembolization brachytherapy oncology consortium. Int J Radiat Oncol Biol Phys 68:13–23.
Lam, M.G.E.H. et al. (2014). Limitations of body
surface area-based activity calculation for
radioembolization of hepatic metastases
in colorectal cancer. J Vasc Interv Radiol
25:1085–1093.
Lambert, B.L. et al. (2011). Urinary excretion of
yttrium-90 following intraarterial microsphere
treatment for liver tumours. J Nucl Med
52(suppl 1):1744.
Metyko, J., Erwin, W., Poston, J. Jr, Jimenez, S.
90
(2014).
Sr content in 90Y-labeled SIR-Spheres
and Zevalin. Health Phys 107:S177–S180.
Metyko, J. et al. (2012). Long-lived impurities
90
of
Y-labeled microspheres, TheraSphere
and SIR-Spheres, and the impact on patient
dose and waste management. Health Phys
103(5S):S204–S208.
References 165
Mo, L. et al. (2005). Development of activity
standard for
90
Y microspheres. Appl Radiat
Isot 63:193–199.
NCRP. (2006). Report 155: Management of
Radionuclide Therapy Patients. Bethesda, MD:
National Council on Radiation Protection and
Measurements.
NCRP. (2010). Report 161: Management of
Persons Contaminated with Radionuclides:
Handbook. Bethesda, MD: National Council
on Radiation Protection and Measurements.
Nelson, K., Vause, P.E., Jr., Koropova, P. (2008).
Post-mortem considerations of yttrium-90
90
(
Y) microsphere therapy procedures. Health
Phys 95(Suppl 5):S156–S161.
NRC. (2007). Yttrium-90 TheraSphere and
SIR-Spheres Impurities: NRC Information
Notice 2007–10. U.S. Nuclear Regulatory
Commission. Washington, DC. Available
from: http://www.nrc.gov/reading-rm/doccollections/gen-comm/info-notices/2007/
in200710.pdf [Accessed October 7, 2011].
NRC. (2008). Consolidated Guidance About
Material Licenses: NUREG-1556 Vol. 9 Rev.
2. U.S. Nuclear Regulatory Commission.
Washington, DC: Ofce of Federal and State
Materials and Environmental Management
Programs. Available from: http://pbadupws.
nrc.gov/docs/ML0734/ML073400289.pdf
[Accessed March 21, 2011].
NRC. (2012). Microsphere Brachytherapy
Sources and Devices: Licensing Guidance –
TheraSphere® and SIR-Spheres® Yttrium-90
ZMicrospheres. Washington, DC: U.S. Nuclear
Regulatory Commission. Available from:
http://pbadupws.nrc.gov/docs/ML1217/
ML12179A353.pdf [Accessed January 14,
2013].
NRC. (2013). 10 Code of Federal Regulations Part
35. Washington, DC: U.S. Nuclear Regulatory
Commission. Available from: http://www.nrc.
gov/reading-rm/doc-collections/cfr/part035/
[Accessed April 25, 2016].
NRC. (2015). Specialty Board(s) Certication
Recognized by NRC under 10 CFR Part
35. U.S. Nuclear Regulatory Commission.
Washington, DC. Available from: http://www.
nrc.gov/materials/miau/med-use-toolkit/
spec-board-cert.html [Accessed March 31,
2016].
Ostrowski, R. et al. (2007). Radionuclidic purity
assessment of yttrium-90 (Y-90) microspheres.
J Nucl Med 48(Suppl 2):2206.
Pasciak, A.S., Erwin, W.D. (2009). Effect of voxel
size and computation method on Tc-99m
MAA SPECT/CT-based dose estimation for
Y-90 microsphere therapy. IEEE Trans Med
Imag 28:1754–1758.
Petitguillaume, A. et al. (2014). Three-dimensional
personalized Monte Carlo dosimetry in
90
Y
resin microspheres therapy of hepatic metastases: Nontumoral liver and lungs radiation
protection considerations and treatment planning optimization. J Nucl Med 55:405 – 413.
Salem, R., Thur ston, K.G. (2006).
Radioembolization with
90
Ytt rium mic rospheres: A state-of-the-art brachytherapy
treatme nt for primary a nd secondar y liver
malignancies. J Vas c Interv Radiol 17:1251–1278.
Siegel, J.A. (2004). Guide for Diagnostic Nuclear
Medicine and Radiopharmaceutical Therapy.
Reston, VA: The Society of Nuclear Medicine
and Molecular Imaging.
Selwyn, R.G. et al. (2007). A new internal pair
production branching ratio of
opment of a non-destructive assay for
90
Sr. Appl Radiat Isot 65:318–327.
90
Y: the devel-
90
Y and
Selwyn, R. et al. (2008). Technical note: The
calibration of
90
Y-labeled SIR-Spheres® using
a nondestructive spectroscopic assay. Med
Phys 35:1278–1279.
Simon, B.A. (2000). Non-invasive imaging of
regional lung function using x-ray computed tomography. J Clin Monit Comput
16:433 –442.
Sirtex Medical Limited. (2003). SIR-Spheres®
Training Program – Physicians and Institutions
[Accessed June 30, 2010].
Sirtex Medical Limited. (2010). Package Insert
– SIR-Spheres® Microspheres (Yttrium-90
Microspheres). Available from: http://www.sir-
tex.com/media/29845/ssl-us-10.pdf [Accessed
August, 2015].
Thieme, K., Beinlich, U., Fritz, E. (2004).
Transferstandard for beta decay radionuclides in radiotherapy. Appl Radiat Isot
60:519–522.
Zanzonico, P.B., Binkert, B.L., Goldsmith, S.J.
(1999). Bremsstrahlung radiation exposure from pure β-ray emitters. J Nucl Med
40:1024–1028.
The radiation biology
ofradioembolization
MARTA CREMONESI, FRANCESCA BOTTA, MAHILA FERRARI, LIDIA
STRIGARI, GUIDO BONOMO, FRANCO ORSI, AND ROBERTO ORECCHIA
8
8.1 Introduction 167
8.2 Basic aspects of radiation biology 169
8.2.1 Repair 169
8.2.2 Repopulation 169
8.2.3 Reoxygenation 169
8.2.4 Redistribution 170
8.2.5 Further considerations specic
to the 4Rs in radioembolization 170
8.3 Radiobiological models 171
8.3.1 The linear quadratic model 171
8.3.2 The biological effective dose 173
8.1 INTRODUCTION
In recent years, the use of dosimetry to support
radionuclide therapy has gained importance as
documented by the increased number of articles addressing dosimetry. e latest literature
reports some remarkable correlations between
absorbed dose delivered, response, and toxicity, which have advanced the understanding of
radiobiological eects. In a recent review published by Strigari et al. (2011), dose–eect relationships were collected and these indicated that
dosimetry-based personalized treatments would
improve outcomes and increase survival and open
the way toward predictivity and personalization
of therapy. Available evidence covers nearly all
widely used nuclear medicine therapies, including
8.3.3 Tumor control probability (TCP) 174
8.3.4 Normal tissue complication
probability 176
8.4 Application of the models and examples 180
8.4.1 NTCP predictions under the
hypothesis of uniform irradiation 188
8.4.2 NTCP predictions for clinical cases
with nonuniform irradiation 190
8.5 Summary for clinical applications 193
8.6 Conclusions 195
References 195
the treatment of dierentiated thyroid cancer and
benign thyroid disease with
131
with
endocrine tumors with
bone pain palliation with
tetramethylene phosphonate (
also radioembolization of primary and secondary
liver cancer with
dose–eect correlations have been provided in the
literature, including a study by Strigari et al. (2010),
which was the rst to describe a model to interpret toxicity and tumor response for hepatocellular carcinoma (HCC) treated with
spheres; studies by Garin et al. (2012, 2015, 2016),
which showed prognostication of tumor response
and survival for HCC treated with
glass microspheres; a study by Chiesa et al. (2015),
I-mIBG (metaiodobenzylguanidine), neuro-
90
Y-microspheres.
In particular for radioembolization, signicant
131
I, neuroblastomas
177
Lu and 90Y radiopeptides,
153
Sm-ethylene diamine
153
Sm-EDTM), and
90
Y-labeled resin
90
Y-labeled
167
168 The radiation biology ofradioembolization
showing dose thresholds for tumor response and
liver toxicity for HCC treated with 90Y-labeled
glass microspheres; and nally a study by Flamen
et al. (2008), showing the prediction of metabolic
response evaluated by multimodality imaging for
metastat ic liver tu mors and 90Y-labeled resin micro spheres. Interestingly, besides providing correlation between dose and eect, these investigations
pointed out apparent and unexpected dierences
in tolerability and response associated with glass
vs. resin 90Y microspheres, which could not be
resolved by invoking the mere concept of absorbed
dose, at least if only the mean absorbed dose at
macroscopic level was considered.
As a whole, the ndings up to now (circa 2016)
highlight the need for more rened models to
improve dosimetry information, and especially,
the importance of radiation biology to dene the
eect of radioembolization on tissue.
As a natural consequence, the rst attempts at
dening radioembolization dose–eect relationships have been extensively compared with the
data from external beam radiotherapy (EBRT). Of
course, in EBRT, the use of radiobiological models is
well established and enables the possibility of comparing eects due to dierent irradiation modalities,
dose rate, dose distribution, organ structure, volume
eect, radiosensitivity, combined therapies, and risk
factors all at the same mean dose. In the clinical
context of radioembolization, outcomes such as the
volume eect, the inuence of the functional reserve
and/or concomitant therapies, a nd higher tolerability
of retreatment have been empirically observed. is
reects a further similarity with EBRT, although differences with EBRT exist and must be taken in mind.
Moreover, three-dimensional (3D) voxel dosimetry
methods at both a macroscopic and microscopic
levels recently applied to radioembolization have
provided dose distribution maps and dose–volume
histograms (DVH) that permit the development of
more rened radiobiological models.
is chapter presents the basic aspects of radiation biology, developed for EBRT and subsequently
adapted to nuclear medicine therapy. e most
widely used radiobiological models will be discussed, including the linear quadratic model with
the biological eective dose (BED) concept, tumor
control probability (TCP), and the normal tissue
complication probability (NTCP) models. ese are
the rst of many acronyms common in radiation
biology which will be introduced in this chapter. A
summary of acronyms is provided in Table8.1.
Table 8.1 Abbreviations and acronyms
BED = biological effective dose
= BED value for 50% complication
BED
50
probability
, BEDRE = BED in EBRT and in RE
BED
EBRT
treatments
CTCAE = Common Terminology Criteria for
Adverse Events
D = absorbed dose
d = absorbed dose delivered in one EBRT
fraction
DVH = dose volume histograms
EASL = European Association for the Study of
the Liver
EBRT = external beam radiotherapy
= relative effectiveness (E
E
rel
= BED/D)
rel
EUD = equivalent effective dose
EUBED = equivalent uniform biological effective
dose
fr = fraction of EBRT
FSU = functional subunits
HCC = hepatocellular carcinoma
LKB model = Lyman–Kutcher–Burman model
msA = microsphere-specic activity
= initial number of clonogenic cells
N
0
NTCP = normal tissue complication probability
QUANTEC = Quantitative Analyses of Normal
Tissue Effects in the Clinic
RE = radioembolization
RECIST = Response Evaluation Criteria in Solid
Tumors
SF = surviving fraction of irradiated cells
T = total duration of exposure
T* = effective time reached when BED = 0
, TD50 = tolerated absorbed dose for 5% or
TD
5
50% complication probability (at 5 years if
, TD
specied by TD
= doubling time of proliferation
T
av
5,5
50,5
)
TCP = tumor control probability
= effective half-life
T
eff
= physical half-life of 90Y
T
phys
= repair half-life
T
rep
V = tumor volume
= effective volume
V
eff
= effective decay constant
λ
eff
= physical decay constant
λ
phys
= repair constant = 0.693/T
μ
rep
rep
8.2 Basic aspects of radiation biology / 8.2.3 Reoxygenation 169
Finally, some explanatory examples on how
radiation biology can guide radioembolization
planning are also given; the most relevant studies
on these issues are briey reported as well.
8.2 BASIC ASPECTS OF
RADIATION BIOLOGY
Radiation biology is the study of the eect of
ionizing radiation on biological tissues. ese
complex eects involve physics, chemistry, and
biology concepts. e most important biological
factors that play a role during irradiation, aecting to some extent the outcome of the treatment,
are summarized by the so-called “4Rs of radiation biology”: repair of DNA damage, redistribution of cells in the cell cycle (spanning a few
hours), repopulation (spanning 5–7 weeks), and
reoxygenation of hypoxic tumor areas (spanning a few hours to few days) Pajonk et al. (2010).
Certainly tumor response is modulated by
many additional factors, and some authors add
the intrinsic radiosensitivity of individual cancer stem cells as the h R, although this may
vary during radiation therapy and needs deeper
investigation.
8.2.1 REPAIR
Ionizing radiation cell killing is a consequence of
unrepairable DNA double-strand breaks. Most
radiation-induced DNA injury is, however, sublethal and may be repaired depending on factors including the type and energy of radiation,
the dose rate, and the phase in the cell cycle. If
radiation is delivered with a low dose rate, the
repair possibility increases, while at increasing
dose rates, sublethal lesions can rapidly accumulate without full repair, contributing to lethality.
Based on the dierent ability of normal tissues and
tumors to repair radiation damage, therapy fractionation is a recurrent strategy in EBRT to spare
normal tissues.
is concept has also been extrapolated to some
nuclear medicine therapies, including radioembolization (Cremonesi et al., 2008), dividing the treatment in cycles to reduce toxicity to late responding
organs at risk. e repair probability is described
as an exponentially decaying function over time,
with half-time (T
hours.
) varying from minutes to few
rep
8.2.2 REPOPULATION
Both tumor and normal tissues have a characteristic proliferation rate that allows tumor
growth and regeneration of some normal tissues
(e.g., the bone marrow and the liver). During
irradiation, repopulation counteracts the cell
killing induced by radiation, so repopulation is
desirable following irradiation of normal tissues
to limit side eects, while it is unwanted in the
case of tumors due to the potential impairment
of treatment.
Keeping in mind that radiation-induced cell
killing includes the loss of the reproductive capability of the cell, it follows that damage becomes
visible when the cell reaches the phase of mitosis:
at that stage, if lethal DNA damage has occurred,
cell replication is prevented. erefore, radiation
response, namely tumor control or organ failure,
arises aer a latency time that is linked to the proliferation rate in that tissue.
In the case of tumors, fast growing tumors may
show a decrease in their growth rate within a few
days aer irradiation, while more indolent tumors
may need weeks or months (HCC) to reduce in
size, but still have the possibility to respond completely to therapy (Withers et al., 1988; Withers,
1992). Similarly, quickly proliferating tissues such
as bone marrow, skin, and intestinal mucosa may
give a warning sign of damage very early aer the
beginning of the treatment. Conversely, slowly
proliferating tissues such as kidney, liver, lung,
and bone may manifest injury aer months or
years.
8.2.3 REOXYGENATION
e oxygen enhancement ratio (OER) refers to
the enhancement of a therapeutic or detrimental
eect of ionizing radiation due to the presence of
oxygen, and is quantitatively dened as the ratio
between the absorbed dose in hypoxic conditions
and normal conditions for a same biological eect.
Oxygen is a potent modier of radiosensitivity and
hypoxic cells are typically two to three times more
resistant to radiation. Tumors typically contain
170 The radiation biology ofradioembolization
regions of transient acute and/or chronic hypoxia,
especia lly in the center due to vasc ulariz ation. ese
tumors have oen been shown to be associated with
a poor prognosis. Moreover, there is evidence that
the duration of hypoxic conditions and the extent
of the hypoxia are inuential factors. Although the
underlying mechanisms are to be further claried,
cells irradiated shortly aer reoxygenation or aer
long-term exposure to hypoxia are more radiosensitive compared with those irradiated aer 4–24
hours of hypox ia.
Reoxygenation between dose fractions is
generally believed to ease the sterilization of
hypoxic cells by increasing tumor radiosensitivity. Reoxygenation mechanisms span a few hours
to few days and typically occur a few days aer the
beginning of irradiation, when the depopulation of
the more radiosensitive cells from the bulk tumor
enables more hypoxic cells to reach the blood vessels, stimulating oxygenation.
8.2.4 REDISTRIBUTION
Cells exhibit a dierent radiosensitivity at dierent phases of the cell cycle, with cells in the early
S- and late-G2/M phase being most sensitive to
ionizing radiation, while cells in late S-phase are
the most resistant. During fractionated radiation
therapy, cells in the G2/M-phase are preferentially
killed, leading to a block of cells in the G2 phase
and to a resulting synchronization of cells in the
radioresistant S-phase. e time interval between
fractions allows resistant cells from the S-phase of
the cell cycle to unsynchronize, redistributing into
phases in which cells of both tumors and normal
tissues are more radiosensitive, thereby increasing the radiation damage. Redistribution eects
span several hours and play an important role
in EBRT, particularly when fractions are spaced
out by several hours. In fact, redistribution during fractionated irradiation allows the sparing of
normal tissues that have few rapidly cycling cells
compared with tumors containing many cells with
rapid turnover.
e eects summarized by the 4Rs have a leading role for the success and optimization of radiation therapy, including radionuclide therapy, and
have represented a landmark for the development
of radiobiological models describing the survival
of cells aer irradiation.
8.2.5 FURTHER CONSIDERATIONS
SPECIFIC TO THE 4Rs IN
RADIOEMBOLIZATION
Radiation therapy using EBRT and radioembolization dier in various aspects. First, in EBRT the
treatment is generally delivered by fractionating
the total dose, e.g., at 2 Gy per fraction (fr), while
in radioembolization treatment is delivered in a
single session and the dose rate decreases over time
due to the physical decay of 90Y. Furthermore, resin
microspheres produce an additional embolic eect
that may contribute to tumor control.
In particular, the use of fractionation in EBRT
permits the redistribution of cells in the hypoxic
and oxic compartment, which generally occurs in
the interval between fractions. is phenomenon
arises during dose delivery in radionuclide therapy but in the case of HCC, cell loss could require
treatments separated by months as reported in the
clinical report assessing tumor response (Kong
and Hong, 2015). e possibility to increase the
oxic levels of tumoral cells present in the hypoxic
area before therapy could be possible during radionuclide therapy.
From another point of view, large hypoxic areas
contribute to the stability of tumor volume over
time. Stability is considered as a form of tumor
control for liver cancer. Moreover, some authors
report that chronic hypoxic areas are more radiosensitive than oxic ones, while the contrary is true
for acute hypoxic areas. In general, from the radiobiological point of view, a tumor can be considered to be constituted of both chronic and acute
hypoxic cells as reported in Strigari et al. (2010).
is means that chronic/acute hypoxic areas could
be damaged by radiation and further that damage may be only partially repaired due to the local
absence of the oxygen.
A positive oxygen eect could occur in radioembolization strategies that plan more than one
cycle. e rst cycle of radioembolization should
provoke a partial tumor shrinkage, potentially
increasing the vascular perfusion to the remaining
tumor. is should facilitate oxygenation and thus
increase radiosensitivity, enhancing the eects of a
subsequent cycle. Such an approach, although clinically more complex, could improve the response
of tumors, compared with a single radioembolization therapy. Increased ecacy is likely, especially
in the case of tumors large in size and with areas
8.3 Radiobiological models / 8.3.1 The linear quadratic model 171
ln(SF) ()
2
DD=−α−β
SF exp( )
2
DD=−α−β
poorly vascularized but not necrotic, or in cases
where potential toxicity to normal tissues is of
concern.
Furthermore, radiotherapy using both external beam and internal emitters is a therapeutic strategy based on the oxidative stress. Both
treatment modalities are specically designed
to increase reactive oxygen levels in tumor cells
to elicit their death through sudden and intense
oxidative stress (Manda et al., 2015). Cancer cells
present a high intrinsic oxidative activity, so less
additional reactive oxygen species are required
compared with normal cells for triggering cell
death. Levels of reactive oxygen species that
are cytotoxic for cancer cells induce less drastic
eects in normal cells, which have a lower oxidative status and are endowed with ecient systems
to repair injuries induced by reactive oxygen
species—within certain limits. Nevertheless,
precise targeting of dose to the diseased tissue is
a priority, aiming to spare normal tissues against
the deleterious action of “therapeutic” reactive
oxygen species. e sparing of normal tissue is
guaranteed in EBRT by the possibility of using
advanced delivery techniques, while in radioembolization it is achieved by selective or superselective administration of radioactive sources
within the liver.
In addition, the macroembolic eect of resin
microspheres is accompanied by a greater lack
of oxygen resulting in ischemia, and therefore,
enhanced ecacy. On the other hand, a shortage
of oxygen might also diminish the tumoricidal
eect of ionizing radiation due to a lack of oxygen radicals. In other words, the embolic eect
and the potential reduction of oxygen free radicals are opposite phenomena and the resulting
nal net eect of these processes is still unclear.
e process of tumor control or normal tissue damage is complex with respect to the currently proposed modeling (Strigari et al., 2011;
Cremonesi et al., 2014). Increased cell damage aer repair signaling can cause mitotic
catastrophe and cell death with an associated
inammatory tissue response. Tissue changes
due to signicant cell death can alter oxygenation status (reoxygenation) and trigger accelerated repopulation and redistribution in the cell
cycle. Finally, tumor heterogeneity derives also
from the nonuniform spatial distribution of
microenvironmental stresses, such as hypoxia,
acidosis, oxidative stress, and nutrient deprivation (Mitsuishi et al., 2012). Unfortunately, these
factors are only partially included in the radiobiological models. Additional studies are needed
to further address these issues.
8.3 RADIOBIOLOGICAL MODELS
8.3.1 THE LINEAR QUADRATIC
MODEL
Among radiobiological models describing the survival of cells aer irradiation, the linear quadratic
model is the most well known.
A cell survival curve describes the relationship
between the fraction of surviving cells (SF), i.e.,
the fraction of irradiated cells that maintain reproductive integrity, and the absorbed dose. Its shape
depends on several factors, including the type of
radiation, the type of cells, and the radiation dose
rate.
e linear quadratic model describes the eect
induced by radiation in a cell population as a function of the dose delivered, and from that, the SF.
e main hypothesis assumed by the linear quadratic model is that the SF of cells receiving an
instantaneous absorbed dose D (as occurs, e.g., in
EBRT) follows the equation:
or, equivalently,
e radiation-induced damage is described by
the sum of two terms, αD and βD2, respectively,
representing
●
DNA irreparable events (double-strand breaks)
in which both strands in the double helix are
simultaneously severed. e number of such
events is proportional to D by the factor α,
which represents the intrinsic radiosensitiv-
ity. α is tissue specic and describes the initial,
linear slope of the SF curve.
●
Two independent DNA reparable events
( single-strand breaks), occurring close enough in
time and space on the DNA lament to gener-
ate cellular death. e number of such events
(8.1)
(8.2)
Соседние файлы в папке Библиотека им академика М.И. Перельмана