Lecture 21
BRACHYTHERAPY
Lecture 21
Ahmed Group
Brachytherapy
-is the internal radiation treatment achieved
by implanting radioactive material directly into the tumor or very
close to it.
Sometimes called internal radiation therapy.
Prefix “brachy” – from Greek for “short range”
Implanting radioactive sources directly into a tumor was a strategy
first suggested by Alexander Graham Bell soon after the turn of the
century.
Lecture 21
Ahmed Group
Brachytherapy
There are two distinct forms of brachytherapy:
1) Intracavitary irradiation using radioactive sources that are
placed in body cavities in close proximity to the tumor and
2) Interstitial brachytherapy using radioactive seeds implanted
directly into the tumor volume.
Lecture 21
Ahmed Group
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Lecture 21
Dose rate effects (HDR and LDR)
Choice of isotopes
Interstitial and intra-cavitary use
Radio-labeled antibodies
BED and Iso-effective dose calculations
Ahmed Group
Low Dose Intracavitary Brachytherapy
Low dose intracavitary brachytherapy (dose rate of about
50cGy/hr, or 50 rad/h) is temporary and usually takes 1 to 4 days.
It is most commonly used for the uterine cervix.
Lecture 21
Ahmed Group
High Dose Intracavitary Brachytherapy
To an increasing extent, low-dose-rate intracavitary
brachytherapy is being replaced by high-dose-rate intracavitary
therapy, delivered in 3 to 12 dose fractions.
This therapy gives up much of the radiobiological
advantage and the sparing of late-responding normal tissues. It
is only possible because the treatment of carcinoma of the
cervix is a special case in which the dose-limiting normal
tissues (e.g. bladder, rectum) receive a lower dose than the
dose to the tumor.
Lecture 21
Ahmed Group
High Dose Intracavitary Brachytherapy
For high-dose-rate treatments lasting a few minutes, it is
possible to sue retractors that result in even lower doses to the
critical normal tissues that are possible with an insertion that lasts
24 hours or more.
These physical advantages offset the radiobiologic
disadvantages, so that the general principle, that administration of
a few large fractions at a high dose rate gives poorer results than a
lower dose rate, dose not apply in this case.
Lecture 21
Ahmed Group
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Lecture 21
Dose rate effects (HDR and LDR)
Choice of isotopes
Interstitial and intra-cavitary use
Radio-labeled antibodies
BED and Iso-effective dose calculations
Ahmed Group
Choice of isotopes
There has been a continual evolution in the radionuclide
used; in the early days, radium was used, but this went out of favor
because of the safety concern of using an encapsulated source that
can leak radioactivity. As an interim measure, cesium-137 was
introduced, but today most treatment centers use iridium-192; its
shorter half-life and lower gamma-ray energy make for ease of
radiation protection, especially in conjunction with a remote after
loader.
Lecture 21
Ahmed Group
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Lecture 21
Dose rate effects (HDR and LDR)
Choice of isotopes
Interstitial and intra-cavitary use
Radio-labeled antibodies
BED and Iso-effective dose calculations
Ahmed Group
Interstitial Brachytherapy
Interstitial brachytherapy can be either temporary or permanent.
Temporary brachytherapy.
Most widely used radionuclide at the present time is iridium-192
Lecture 21
Ahmed Group
Temporary Brachytherapy.
5% or so of human cancers are accessible to such technique. The
dose-rate used is in the region of the dose-rate spectrum in which
the biologic effect varies rapidly with dose rate.
Lecture 21
Ahmed Group
Temporary Brachytherapy.
In the 1990s, Mazeron and his colleagues published two
papers that show clearly that a dose-rate effect is important in
interstitial implants.
Lecture 21
Ahmed Group
Temporary Brachytherapy.
Their second report analyzes data from a large group of patients
with carcinoma of the breast who received iridium-192 implants as
a boost to external-beam radiotherapy. These results allow an
assessment of the effect of dose rate only on tumor control, but no
information on dose rate on late effects, so only limited
conclusions can be drawn from the data.
The results (next slide), however, show a correlation between the
proportion of recurrent tumors and the dose rate.
Lecture 21
Ahmed Group
Temporary
Brachytherapy.
For a given total dose,
there were markedly
fewer recurrencies if the
radiation was delivered at
a higher dose rate rather
than a lower dose rate.
Lecture 21
Ahmed Group
Temporary Brachytherapy.
The relatively short half-life of iridium-192 (70 days) means
that a range of dose rates is inevitable. It is important,
therefore, to correct the total dose rate.
Iridium-192 has two advantages:
1) The source size can be small, and
2) Its lower photon energy makes radiation
protection easier than with radium or cesium-137
Lecture 21
Ahmed Group
Temporary Brachytherapy.
Sources of this
radionuclide are
ideal for use with
computercontrolled remote
afterloaders
introduced in
1990s.
Lecture 21
Ahmed Group
Permanent Interstitial Implants
Encapsulated sources with relatively short half-life can be
left in place permanently. There are two advantages for the
patient:
1) An operation to remove the implant is not needed,
2) the patient can go home with the implant in place.
Iodine-125 has been used most widely to date for permanent
implants.
The total prescribed dose is usually about 160 Gy at the periphery
of the implanted volume, with 80 Gy delivered in the first
half-life of 60 days.
A major advantage of iodine-125 is the low energy of the photons
emitted (about 30 keV).
Lecture 21
Ahmed Group
Permanent Interstitial Implants
A number of other new radionuclides are under consideration
as sources for brachytherapy that share with iodine-125 the
properties of a relatively short half-life and low-energy photon
emission to reduce problems of radiation protection.
Lecture 21
Ahmed Group
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Lecture 21
Dose rate effects (HDR and LDR)
Choice of isotopes
Interstitial and intra-cavitary use
Radio-labeled antibodies
BED and Iso-effective dose calculations
Ahmed Group
Radio-labeled antibodies
Radio-labeled immunoglobulin therapy is radiotherapy for cancer
using an antibody to deliver a radioactive isotope to the tumor.
Much of the pioneering work in this field was done by Stanley
Order and his colleagues in the 1980s, with the primary focus on
anti-ferritin labeled with radioactive iodine or yttrium. Although
ferritin is also present in normal tissues, selective tumor targeting
has been demonstrated in animal models and in clinical scanning,
historically performed first for Hodgkin’s disease. This differential
is the basis of the potential therapeutic gain in radio-labeled
immunoglobulin therapy.
Radio-labeled murine monoclonal antibodies (in oppose to earlier
used polyclonal antibodies) carrying iodine-131, are being currently
used for both diagnosis and therapy. More recently, chimeric
mouse-human antibodies have become available for radiotherapy
Lecture 21
Ahmed Group
Radiolabeled antibodies
In the last 20 years new tumor markers have been described as a
result of developments in the field of protein chemistry and
hybridoma technology. Antibodies to tumor-related products are
regularly used to assist the histological and serological diagnosis of
many types of cancer and monitor therapy.
A further and very exciting role of antibodies is to act as vehicles
to target therapy to tumors. The possibility of investigating the use
of these antibodies to target tumors has been greatly assisted by
techniques such as human xenografts in animals.
Lecture 21
Ahmed Group
Radiolabeled antibodies
There are two general strategies that can be employed for
therapeutic antibody targeting. One is serotherapy which uses the
host’s immune system to interact with the anti-tumor antibody to
kill tumor cells. In the other and more frequently used approach a
cytocidal agent is conjugated to an antibody which carries the
compound to the tumor.
Lecture 21
Ahmed Group
Radionuclide conjugates
The selection of a particular radionuclide depends on tumor size.
High energy beta-radiation is best suited to larger tumors where
neighbouring areas may benefit from cross-fire effects. However,
it is not clear whether the different characteristics of radio-nuclides
are sufficiently important to produce significant therapeutic
differences in the results of radio-immunotherapy.
Despite potential radiobiological advantages there are practical
considerations that influence the choice of radionuclide.
Lecture 21
Ahmed Group
Radionuclide conjugates
For example conjugation of a radionuclide to an antibody must not adversely
affect the ability of the immuno-conjugate to bind to the tumor.
Lecture 21
Ahmed Group
Clinical trials with radio-labeled antibodies
Radio-labeled antibodies have now been used to treat many types
of cancer.
Therapeutic studies with radio-labeled antibodies:
Intravenous:
Hepatoma
Lymphoma
Colorectal cancer
Melanoma
Neuroblastoma
Intraperitoneal/Intrapleural
Ovarian cancer
Lung cancer
Intra-thecal
Neuroblastoma
Malignant meningitis
Intra-arterial
Glioma
Lecture 21
Ahmed Group
Clinical trials with radio-labeled antibodies
Significant responses have been seen in advanced colorectal cancer
and melanoma, two tumors generally regarded as relatively
insensitive to radiation.
Lecture 21
Ahmed Group
Clinical trials with radiolabeled antibodies
Phase I dose escalating
studies have determined the
dose-limiting toxicity of
radio-labeled
antibodies,
and serial measurements of
radioactivity (made from
external
scintigraphic
images) have been used to
study the distribution of
radioactivity in tissues and
tumor and to make estimates
of the radiation dose.
Lecture 21
Ahmed Group
Clinical trials with radio-labeled antibodies
Example: administration
of 50 Ci of iodine-131
labelled anti-CEA to
patients with recurrent
colorectal cancer.
The best tumor response
was seen in the patient
who had the greatest
concentration
of
the
radioactivity in the tumor,
and the most favorable
ratio of radioactivity in
the tumor relative to other
tissues.
Lecture 21
Ahmed Group
Limitations of
Radio-labeled
antibodies
therapy
Antibody
delivery
antibody uptake local
tissue factors toxicity.
Myelo-toxicity is the
principal side effect of
radio-immunotherapy that
limits both the dose and
interval between courses
of therapy.
Lecture 21
Ahmed Group
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Lecture 21
Dose rate effects (HDR and LDR)
Choice of isotopes
Interstitial and intra-cavitary use
Radio-labeled antibodies
BED and Iso-effective dose calculations
Ahmed Group
BED and Iso-effective dose calculations
It is often useful in practice to have a simple way to compare different
fractionation regimens and to assign them a numeric score. The
linear-quadratic model is now widely used.
Lecture 21
Ahmed Group
BED and Iso-effective dose calculations
The ratio α/β has the dimensions of dose and is the dose at which the
linear and quadratic components of cell killing are equal.
For a single acute
dose D, the biologic
effect is given by
Lecture 21
Ahmed Group
BED and Iso-effective dose calculations
Lecture 21
Ahmed Group
BED and Iso-effective dose calculations
Lecture 21
Ahmed Group
BED and Iso-effective dose calculations
Calculating the examples: ratio α/β is assumed to be 3 Gy for lateresponding tissues and 10 Gy for early-responding tissues.
Lecture 21
Ahmed Group
Model calculations
Lecture 21
Ahmed Group
Model calculations
Lecture 21
Ahmed Group
Model calculations
Lecture 21
Ahmed Group