We calculated the yeald in IPEN/CNENSP reactor, IEA-R1 built in 1956. This reactor outputs around 4.5MW and the thermal flux is 8.1012 n/cm2.s at the xenon/iodine capsule position. After the cycle of irradiation (64 hours) we will have 65 GBq of iodine-125. In this time we will have around 0.26% of iodine-126 produced. After 20 days, the activity of iodine-125 will be 50 GBq and 0.14% of iodine-126. After 40 days, we yield 40 GBq of I-125

The second technique used to produce iodine-125 is the continuous production using a cryogenic system with circulating liquid nitrogen. This technique consists in two capsules: one inside the reactor core and the second one out of the neutron flux. These two capsules will be linked with two cryogenic pumps to guarantee that all iodine-125 produced in the core will be take off the reactor core (Figure1). The cryogenic temperature, around 77 K, will turn the iodine liquid but the xenon will be pumped again to the core in gaseous form. After the irradiated cycle, we take up and seal the capsule outside of the core, and consequently yield almost onlyiodine (with a traces of xenon),) and insert another Xenon-124 enriched capsule in the reactor to continue the production. The greatest disadvantage of this technique is the using of two positions in the core of the reactor though Brazil has only one radioisotope reactor producing, andthere is a huge quantity of materials to be produced. Though the current seeds production power in Brazil is only for 3000 seeds per month, though the demand is around 3.5 Ci (around 1.3.1011 Bq) per month. This batch production may produce a small quantity, but this is

Iodine-125 decays by electron capture (EC) and internal conversion to Tellurium-125 as shown in figure 2. Photons with 27 keV, 31 keV and 35 keV (average 29 keV) are issued.

50% to 34% imediately after the reactor shutdown.

with 0.06% of iodine-126.

more than that of batch production.

2008].

system.

Fig. 1. Iodine-125 production system in cryogenic method [Zeituni et. Al., 2011]. (To publisher, this is too small. To authors, please indicate how to use this unit showing or describing the corresponding reactor part or position: for exapmle, "The reactor capsule part is placed into the reactor core." The figure is not enough to explain how to retrieve the capsule, where to insert next capsule, where to take up the I-125.)

Fig. 2. Iodine-125 decay scheme [Baltas et. Al, 2006]

#### **3. Iodine-125 seeds**

Iodine-125 sources are used in the radiotherapy of brain, neck, lung, pancreas and prostate cancers, as well as intraocular tumors (choroidal melanomas and retinoblastomas). They can

Theoretical, Manufacturing and Clinical

seed is sealed by laser.

coating. A silver bullet is placed inside the cylinder.

adsorbed by ion exchange resin in five balls.

on the resin pellets with a diffusion barrier.

some of them were not commercialized.

**4. Dosimetry of Iodine-125 seeds**

references [Nath et. al., 1995; Rivard et. al. 2004].

length (region that radioactive material was distributed).

*o)* that provides the reference dose rate *D(r,*

with any chosen point *P(r,*

*P(ro,*

the source. It is used a marker of iridium and platinum.

silver is used. A marker containing 10% platinum is used.

source.

Application Aspects of a Prostate Brachytherapy I-125 Source in Brazil 65

Syncor (China) PharmaSeed BT-125-I: Iodine-125 is adsorbed on palladium wire. The

Med-Tec - Implant Sciences (USA) I-Plant 3500: Iodine-125 is deposited on a ceramic

 International Brachytherapy (Belgium) Intersource Iodine-125L. Iodine-125 is adsorbed on the inorganic matrix ring positioned in the center and beads at the ends of

UroCor – Mills Biopharmaceuticals (USA) ProstaSeed I125-SL: Iodine-125 is

Imagyn Medical – International Isotope (USA) IsoSTAR 1250I: Iodine-125 is adsorbed

DraxImage – Cytogen (Canada) BrachySeed LS-1: A glass substrate doped with

It is important to notice that some seeds shown under here are not produced nowadays and

The dosimetric characteristics of the iodine-125 seeds are performed according to American Association of Physics in Medicine (AAPM) formalism Task Group No. 43(TG-43). This protocol was developed by a committee of brachytherapy dosimetry researchers and implements specific modifications on the physical quantities assigned to the brachytherapy sources, these measurable quantities are used to obtain the dose distribution of the brachytherapy sources [Nath et. al., 1995]. TG-43 underwent an update rendering to the TG-43U1 [Rivard et. al. 2004] and a supplement were published afterwards [Rivard et. al. 2007]. TG-43U1 dose rate calculation will be briefly described here but the details are found in the

Basically, TG-43U1 recommends that the dosimetry distribution of brachytherapy sources will be performed with experimental and computational methods. Experimental methods usually use thermoluminescent dosimetry methods [Chiu-Tsao et. al. 1990; Nath and Yue 2002; Wallace 2000]. The majority of computational methods uses Monte Carlo (MC) radiation transport codes, for example, EGSnrc, MCNP, Geant, PENELOPE and others

For both experimental and computational methods, the formalism to calculate the dose rates is based in one (1D) and a two-dimensional (2D) configuration. One-dimensional is an approximation for the isotropic point-source. Two-dimensional approximation considers a homogeneous radioactive material distribution along the longitudinal axis of seed active

TG-43U1 two-dimensional approximation is described by polar coordinates around a transversal bisector plane of the source. The dose rate surround the source are determined

*)* on the transversal bisector plane. There is a reference point

*)*; the reference point has distance (*r0*) and

[Burns and Raeside 1987; Mobit and Badragan 2003; Thomson and Rogers 2009].

contains two inactive gold beads which serve as markers to identify and locate the

be used in two different ways – permanent and temporary implants.. Iodine-125 seeds are indicated for the treatment of tumors that have some of the following characteristics: localized, slow growth rate and low to moderate sensitivity. They are also indicated for the treatment of recurrent and residual tumors following a course of external radiation therapy. The mean apparent activity of Iodine-125 seed required to be used in ophthalmic applicators is 20 mCi (740 MBq) and in other applications most often 4-5 mCi (148-185 MBq).

The treatment of prostate cancer with permanent iodine-125 seed implantation has grown dramatically in the world in recent years.

The technique is being used by hospitals and private clinics also in Brazil. Nowadays, the seeds are imported at a minimum cost of US\$ 65.00 per one seed, however the high cost makes them impracticable for use in public hospitals. In a typical prostate brachytherapy 80- 120 seeds are required. Generally, the seeds are composed of a titanium capsule of 0.8 mm outer diameter, 0.05 mm wall thickness and 4.5 mm in length. The internal structure varies significantly by commercial models. Some constitute of resin or ceramic embedding mixture, and others are deposited in a substrate radio-opaque substrate. Commercially available applicator devices for implantation are disigned for the general dimension.

All seeds are encapsulated in titanium because it is an inert material that does not cause rejection when in direct contact with human tissue and it is classified as biocompatible material. The seed manufacturers in the world are concentrated in the United Kingdom, Belgium and the United States of America and the seeds produced differ in the process used in manufacturing, being unique and protected by patents.

The iodine-125 seeds are classified as sealed radioactive sources as standard *International Standard Organization. Radiation Protection – Sealed Radioactive Sources – General Requirements and Classification ISO-2919.*

The seed is formed by a core that has the radioactive material attached; it is wrapped in a shell of biocompatible material sealed on both sides. A radiological marker must also be inserted. Some examples are materials used in the items below [Rostelato, 2006]:

be used in two different ways – permanent and temporary implants.. Iodine-125 seeds are indicated for the treatment of tumors that have some of the following characteristics: localized, slow growth rate and low to moderate sensitivity. They are also indicated for the treatment of recurrent and residual tumors following a course of external radiation therapy. The mean apparent activity of Iodine-125 seed required to be used in ophthalmic applicators

The treatment of prostate cancer with permanent iodine-125 seed implantation has grown

The technique is being used by hospitals and private clinics also in Brazil. Nowadays, the seeds are imported at a minimum cost of US\$ 65.00 per one seed, however the high cost makes them impracticable for use in public hospitals. In a typical prostate brachytherapy 80- 120 seeds are required. Generally, the seeds are composed of a titanium capsule of 0.8 mm outer diameter, 0.05 mm wall thickness and 4.5 mm in length. The internal structure varies significantly by commercial models. Some constitute of resin or ceramic embedding mixture, and others are deposited in a substrate radio-opaque substrate. Commercially

All seeds are encapsulated in titanium because it is an inert material that does not cause rejection when in direct contact with human tissue and it is classified as biocompatible material. The seed manufacturers in the world are concentrated in the United Kingdom, Belgium and the United States of America and the seeds produced differ in the process used

The iodine-125 seeds are classified as sealed radioactive sources as standard *International Standard Organization. Radiation Protection – Sealed Radioactive Sources – General Requirements*

The seed is formed by a core that has the radioactive material attached; it is wrapped in a shell of biocompatible material sealed on both sides. A radiological marker must also be

 UroMed Corporation – Bebig GmbH (Germany) Symmetra-125.S06: Titanium capsule sealed laser, containing a radio-opaque gold wire inside, and a ceramic layer

 Best Medical International (USA) Model 2301: The outer coat consists of double encapsulated titanium, without specifying the type of welding. The interior accommodates a marker of tungsten and iodine-125 adsorbed on an unspecified

 BARD - SourceTech Medical (USA) BrachySource STMIodine-125: The capsule is titanium welded by laser equipment. Inside of the seed has a gold wire as a marker, a layer of aluminum and a "coating" of copper. Iodine-125 is deposited in a cylinder of

Oncura GE Healthcare (USA) OncoSeed 6711: Radio-opaque silver core, where

Oncura GE Healthcare (USA) OncoSeed 6702: Iodine-125 is adsorbed on ion exchange

 Mentor Corp. – North American Scientific (USA) IoGold MED3631-A/M: Titanium capsule sealed by laser. Iodine-125 adsorbed onto four resin beads. The capsule shell

iodine-125 is adsorbed and the outer shell is titanium with laser sealing.

inserted. Some examples are materials used in the items below [Rostelato, 2006]:

available applicator devices for implantation are disigned for the general dimension.

is 20 mCi (740 MBq) and in other applications most often 4-5 mCi (148-185 MBq).

dramatically in the world in recent years.

*and Classification ISO-2919.*

with iodine-125.

substrate.

in manufacturing, being unique and protected by patents.

aluminum with a gold core and a layer of nickel.

resin beads. The outer shell is titanium with laser sealing.

contains two inactive gold beads which serve as markers to identify and locate the source.

It is important to notice that some seeds shown under here are not produced nowadays and some of them were not commercialized.

### **4. Dosimetry of Iodine-125 seeds**

The dosimetric characteristics of the iodine-125 seeds are performed according to American Association of Physics in Medicine (AAPM) formalism Task Group No. 43(TG-43). This protocol was developed by a committee of brachytherapy dosimetry researchers and implements specific modifications on the physical quantities assigned to the brachytherapy sources, these measurable quantities are used to obtain the dose distribution of the brachytherapy sources [Nath et. al., 1995]. TG-43 underwent an update rendering to the TG-43U1 [Rivard et. al. 2004] and a supplement were published afterwards [Rivard et. al. 2007]. TG-43U1 dose rate calculation will be briefly described here but the details are found in the references [Nath et. al., 1995; Rivard et. al. 2004].

Basically, TG-43U1 recommends that the dosimetry distribution of brachytherapy sources will be performed with experimental and computational methods. Experimental methods usually use thermoluminescent dosimetry methods [Chiu-Tsao et. al. 1990; Nath and Yue 2002; Wallace 2000]. The majority of computational methods uses Monte Carlo (MC) radiation transport codes, for example, EGSnrc, MCNP, Geant, PENELOPE and others [Burns and Raeside 1987; Mobit and Badragan 2003; Thomson and Rogers 2009].

For both experimental and computational methods, the formalism to calculate the dose rates is based in one (1D) and a two-dimensional (2D) configuration. One-dimensional is an approximation for the isotropic point-source. Two-dimensional approximation considers a homogeneous radioactive material distribution along the longitudinal axis of seed active length (region that radioactive material was distributed).

TG-43U1 two-dimensional approximation is described by polar coordinates around a transversal bisector plane of the source. The dose rate surround the source are determined with any chosen point *P(r,)* on the transversal bisector plane. There is a reference point *P(ro,o)* that provides the reference dose rate *D(r,)*; the reference point has distance (*r0*) and

Theoretical, Manufacturing and Clinical

phantoms [Meigooni et. al., 1988].

slabs provide backscatter conditions

simulations, according TG43U1 recommendations.

Application Aspects of a Prostate Brachytherapy I-125 Source in Brazil 67

with the minimum uncertainties. This accuracy is important because the rate dose values in the specific point will be employed in the dosimetric calculations treatment planning. These values obtained from experimental measurements must be compared with the MC

For experimental studies, the dosimetric laboratory uses LiF:Mg,Ti (TLD-100) thermoluminescent dosimeters purchased by Thermo Scientific (Harshaw-Bricon). TLD-100 is widely used in the brachytherapy dosimetric investigations for many years [Meigooni et. al., 1988; Nath et. al., 1990; Abboud et. al., 2010]. These dosimeters can be presented in many formats and shapes; the micro-cube format with 1 mm x 1 mm x 1 mm was chosen. These dimensions avoid high gradient fields negligible due to the larger dosimeters dimensions.

To obtain precise dose information of the seed we set TLD-100 micro-cubes around of a single iodine-125 seed in a phantom material that represents liquid water. For the iodine-125 seed emitting low energy photons (average energy 28.37 keV) [Usher-Moga et. al., 2008], the Solid WaterTM phantom material showed better agreements with liquid water compared with other phantoms materials such as Polymethilmethacrilate (PMMA) and others plastics

Figure 4 shows a Solid WaterTM slab of 30 cm x 30 cm x 2 cm in size used in the dosimetric measurements. The slabs were drilled to accommodate the dosimeters in the radial positions in 100 mm of interval, yielding 36 holes per circumference. The hole radial distances along the center of the slab vary from 0.5 cm to 10 cm (Figure 4). The geometry in this seed positioning was to determine the functions of the TG-43 protocol. During the measurement, additional slabs placed above and below the slab containing the seed and dosimeters, these

Fig. 4. Solid WaterTM slab designed for experimental dosimetric measurements [Zeituni 2008].

angle (*0*) equal to one centimeter and /2 radians, respectively. This reference point was chosen according to traditional dosimetry practices [Nath et. al., 1995]. Fig. 3 illustrates the geometry used for brachytherapy source geometry.

Fig. 3. Geometry used to perform the brachytherapy sources dose measurements, the L denotes the source active length (adapted from Rivard et. al., 2004**)**

According to the TG-43U1, the general two-dimensional dose rate formalism for brachytherapy sources can be expressed as:

$$\dot{D}(r,\theta) = \mathbf{S}\_k \cdot \Lambda \cdot \frac{\mathbf{G}\_L(r,\theta)}{\mathbf{G}\_L(r\_0,\theta\_0)} \cdot \mathbf{g}\_L(r) \cdot \mathbf{F}(r,\theta)$$

where *Sk* is the air kerma strength ( 2 1 *cGy cm h* or U), is the dose constant rate ( 2 *cm* ), (, ) *G r L* geometry function; ( ) *L g r* Radial dose function; *F r*(, ) anisotropy function. The subscript L denotes the line-source approximation (2D approximation).

Air kerma strength is determined by a single brachytherapy source model, i.e., each brachytherapy seed model has air kerma strength. This quantity is measured by a standard wide-angle free-air chamber (WAFAC) available in National Institute of Standards and Technology (NIST) laboratory [Seltzer et. al. 2003]. Dose constant rate is the ratio of the dose rate in the reference point ( ( , ) *D r* ) and the air kerma strength. The geometry function is used to calculate the relative dose due to the spatial distribution of the activity within the source; this function does not consider the scattered and attenuated photons in the source. Scattered and attenuated photons effects are accounts for radial dose function along the transverse seed axis with constant angle ( 2 ). Anisotropy function quantify the dose distribution differences due to seed external structure, as the welds on the seeds' extremities [Ravinder et. al., 2004; Nath et. al., 1995]; scattering and absorption effects are included in this function.

Beyond the Sk and (, ) *G r L* functions, that are obtained from standards laboratories and analytical calculations, respectively, the other functions require the dose rate measurements in the point analyzed. So, the aim of the dosimetric laboratory for brachytherapy sources is to measure the experimental dose in the points-of-interest around the transversal plane seed

chosen according to traditional dosimetry practices [Nath et. al., 1995]. Fig. 3 illustrates the

Fig. 3. Geometry used to perform the brachytherapy sources dose measurements, the L

According to the TG-43U1, the general two-dimensional dose rate formalism for

where *Sk* is the air kerma strength ( 2 1 *cGy cm h* or U), is the dose constant rate ( 2 *cm* ),

Air kerma strength is determined by a single brachytherapy source model, i.e., each brachytherapy seed model has air kerma strength. This quantity is measured by a standard wide-angle free-air chamber (WAFAC) available in National Institute of Standards and Technology (NIST) laboratory [Seltzer et. al. 2003]. Dose constant rate is the ratio of the dose

to calculate the relative dose due to the spatial distribution of the activity within the source; this function does not consider the scattered and attenuated photons in the source. Scattered and attenuated photons effects are accounts for radial dose function along the transverse seed

due to seed external structure, as the welds on the seeds' extremities [Ravinder et. al., 2004;

analytical calculations, respectively, the other functions require the dose rate measurements in the point analyzed. So, the aim of the dosimetric laboratory for brachytherapy sources is to measure the experimental dose in the points-of-interest around the transversal plane seed

Nath et. al., 1995]; scattering and absorption effects are included in this function.

0 0 (, ) (, ) () (, ) (, ) *L k L L G r Dr S g r Fr G r*

anisotropy function. The

) and the air kerma strength. The geometry function is used

2 ). Anisotropy function quantify the dose distribution differences

functions, that are obtained from standards laboratories and

denotes the source active length (adapted from Rivard et. al., 2004**)**

geometry function; ( ) *L g r* Radial dose function; *F r*(, )

subscript L denotes the line-source approximation (2D approximation).

brachytherapy sources can be expressed as:

rate in the reference point ( ( , ) *D r*

axis with constant angle (

Beyond the Sk and (, ) *G r L*

geometry used for brachytherapy source geometry.

*0*) equal to one centimeter and /2 radians, respectively. This reference point was

angle (

(, ) *G r L*

with the minimum uncertainties. This accuracy is important because the rate dose values in the specific point will be employed in the dosimetric calculations treatment planning. These values obtained from experimental measurements must be compared with the MC simulations, according TG43U1 recommendations.

For experimental studies, the dosimetric laboratory uses LiF:Mg,Ti (TLD-100) thermoluminescent dosimeters purchased by Thermo Scientific (Harshaw-Bricon). TLD-100 is widely used in the brachytherapy dosimetric investigations for many years [Meigooni et. al., 1988; Nath et. al., 1990; Abboud et. al., 2010]. These dosimeters can be presented in many formats and shapes; the micro-cube format with 1 mm x 1 mm x 1 mm was chosen. These dimensions avoid high gradient fields negligible due to the larger dosimeters dimensions.

To obtain precise dose information of the seed we set TLD-100 micro-cubes around of a single iodine-125 seed in a phantom material that represents liquid water. For the iodine-125 seed emitting low energy photons (average energy 28.37 keV) [Usher-Moga et. al., 2008], the Solid WaterTM phantom material showed better agreements with liquid water compared with other phantoms materials such as Polymethilmethacrilate (PMMA) and others plastics phantoms [Meigooni et. al., 1988].

Figure 4 shows a Solid WaterTM slab of 30 cm x 30 cm x 2 cm in size used in the dosimetric measurements. The slabs were drilled to accommodate the dosimeters in the radial positions in 100 mm of interval, yielding 36 holes per circumference. The hole radial distances along the center of the slab vary from 0.5 cm to 10 cm (Figure 4). The geometry in this seed positioning was to determine the functions of the TG-43 protocol. During the measurement, additional slabs placed above and below the slab containing the seed and dosimeters, these slabs provide backscatter conditions

Fig. 4. Solid WaterTM slab designed for experimental dosimetric measurements [Zeituni 2008].

Theoretical, Manufacturing and Clinical

**5. Introduction for hospital methodology**

gradient temperature.

Dyk, 1999].

Conference in 1988 [Lee, 2003].

stage disease [Halperin et. al., 2008].

**5.1 Brachytherapy process at the Albert Einstein hospital**

possible, are explained to the patient mainly by the urologist.

Application Aspects of a Prostate Brachytherapy I-125 Source in Brazil 69

adopted for the dosimeters is composed by two steps: a) 400ºC for one hour and b) 100ºC for two hours. The thermal variations are performed using the slow cooling rates of approximately 4ºC.min-1 [Oster et. al., 2010]. A special oven was designed for the laboratory to attend the slow cooling rates. This oven has coupled cooler that realizes a linear temperature reduction automatically. During the temperature reduction the dosimeters stay inside the oven avoiding drastic changes in the crystal of the dosimeter caused by the

For adenocarcinoma of the prostate conventional treatment options that should be discussed with each patient in this category include radical prostatectomy, external beam radiation therapy, interstitial brachytherapy and watchful waiting, according to the NCI Consensus

There are two types of prostate cancer radiation treatments: external and internal (interstitial). Brachytherapy is the interstitial one, meaning treatment is administered "within the tissue." External radiation therapy involves the projection of photon, electron, neutron, or proton

Ionizing radiation is used in the treatment of prostate cancer because exposure to this radiation damages the DNA of cells. Cells will not be damaged unless they attempt to divide. Cancerous cells divide more quickly than healthy cells. Therefore, healthy cells are able to repair damage before undergoing mitosis, while cancerous cells are not. Unfortunately, if the absorbed dose is strong enough, healthy cells will be damaged to the point where they cannot repair themselves before division. Interstitial brachytherapy is able to deliver higher doses of radiation to an area concentrated within the prostate gland [Van

The use of brachytherapy as the sole modality of treatment for early-stage prostate cancer has gained popularity over the past decade due to the advent of the transrectal ultrasoundguided technique (TRUS) and the favorable reports of imaged-based brachytherapy with isotope Iodine-125 (I-125). At the same time, dose escalation 3-dimensional conformal radiation therapy (3D CRT) has revealed promising results, especially for patients with early

Initially the patient is referred to radiotherapy or search for a consultation with a radiation oncologist which defines the treatment plan in conjunction with the urologist involved in the process. The evaluation of radiotherapy will consist of complete history, complete physical examination including digital rectal examination, analysis of all imaging (transrectal ultrasound, computed tomography, magnetic resonance imaging, and / or chest radiography) and laboratory (complete blood count with coagulation, all measures of serum PSA). Additional investigations may be required to meet specific needs of each patient (diabetes, epilepsy, heart disease, renal disease, lung disease, etc). Therapeutic options, including observation, hormone therapy, radical prostatectomy, external beam radiotherapy or implantation of Iodine-125 seeds as well as acute and late side effects, expected or

beams into the prostate gland from a remote tool called the linear accelerator.

Before the dosimetric measurements, the TLD-100 dosimeters were previously selected from a dosimeters' batch. The selected dosimeters represent the minimal uncertainties compared with the overall batch. Difference of the dosimeters masses and edges on the dosimetry structure were some parameters analyzed at the selection [Furreta and Weng, 1998].

All thermoluminescent dosimeters yield different responses of the absorbed dose rate quantity. For dosimeter responses in absorbed dose units, a calibration factor makes useful. This calibration factor is obtained from calibrated beams with a traceable reference dosimetry system, as ionization chambers with special requirements.

The range of the dose delivered in the dosimeters was closed to the absorbed dose levels that will be used in experimental dosimetry routine with brachytherapy sources, it ranges from 10 to 100 cGy. Each dosimeter used in the dosimetry has an individual calibration factor, i.e., one value for the calibration factor to the whole batch was not adopted due to reduce uncertainties propagations on the dose rate calculations. These calibration factors obtained from the x-rays photons were calculated by the averaged measurements originated from the dose levels (10 – 100 cGy).

In summary, the dosimeters that will be measure in a TLD reader will yield thermoluminescent responses in arbitrary units. The intensity of these responses will be proportional to the absorbed dose in the dosimeter. To convert TLD's responses in absorbed dose rates quantities the following formula is applied:

$$\frac{\dot{D}(r,\theta)}{S\_k} = \frac{R}{T \cdot S\_k \cdot \varepsilon \cdot E(r) \cdot d(T) \cdot F\_{lin}}$$

where ( , ) *D r* is dose rate ( 1 *cGy h* ) at any point with coordinates (, ) *r* , *Sk* : initial iodine-125 seed air kerma strength ( 2 1 *cGy cm h* ) at the start of the measurements; R: the net dosimeter response (nC) of each measured point with backgrounds subtractions,T: irradiation duration (h), : calibration factor (nC.cGy-1) for each TLD-100, *E r* : a dimensionless correction factor of the TLD-100 between the calibration beam and the iodine-125 photons and the assumed the value was 1.4 for this expression [Abboud et. al., 2010; Reniers et. al., 2002], *d T* : a correction factor that explains the source decay during the TLD-100 irradiations and *Flin* represents a correction for non-linearity in TLD response and was assumed to be unity due to linear response in the doses (10 to 100 cGy) measured with iodine brachytherapy seeds [Meigooni et. al., 2006].

For the TLD-100 measurements a Harshaw 3500 TLD reader is used. The reader operates one dosimeter per load and with continuous flux of pure nitrogen (99,9995% of purity). Nitrogen fluxes are necessary to avoid the signals not delivered from the thermoluminescence dosimeter, as oxygen air induces signals. Heating rate of 10 oC.s-1 and maximum temperature of 260oC are the parameters of TLD-100 measurements used [Thermo Electron Corporation, 2002]. The measurements are performed 20 hours after the exposure; this delay is to avoid unstable glow peak which decays.

TLD-100 dosimeters demand thermal treatments to be reused. Theoretically, the thermal treatment will quench the dose information of previously irradiations. The thermal treatment adopted for the dosimeters is composed by two steps: a) 400ºC for one hour and b) 100ºC for two hours. The thermal variations are performed using the slow cooling rates of approximately 4ºC.min-1 [Oster et. al., 2010]. A special oven was designed for the laboratory to attend the slow cooling rates. This oven has coupled cooler that realizes a linear temperature reduction automatically. During the temperature reduction the dosimeters stay inside the oven avoiding drastic changes in the crystal of the dosimeter caused by the gradient temperature.

### **5. Introduction for hospital methodology**

68 Brachytherapy

Before the dosimetric measurements, the TLD-100 dosimeters were previously selected from a dosimeters' batch. The selected dosimeters represent the minimal uncertainties compared with the overall batch. Difference of the dosimeters masses and edges on the dosimetry

All thermoluminescent dosimeters yield different responses of the absorbed dose rate quantity. For dosimeter responses in absorbed dose units, a calibration factor makes useful. This calibration factor is obtained from calibrated beams with a traceable reference dosimetry system, as ionization chambers with special requirements. [Meigooni et. al., 2001;

The range of the dose delivered in the dosimeters was closed to the absorbed dose levels that will be used in experimental dosimetry routine with brachytherapy sources, it ranges from 10 to 100 cGy. Each dosimeter used in the dosimetry has an individual calibration factor, i.e., one value for the calibration factor to the whole batch was not adopted due to reduce uncertainties propagations on the dose rate calculations. These calibration factors obtained from the x-rays photons were calculated by the averaged measurements originated

In summary, the dosimeters that will be measure in a TLD reader will yield thermoluminescent responses in arbitrary units. The intensity of these responses will be proportional to the absorbed dose in the dosimeter. To convert TLD's responses in absorbed

*k k lin*

*S T S Er dT F*

125 seed air kerma strength ( 2 1 *cGy cm h* ) at the start of the measurements; R: the net dosimeter response (nC) of each measured point with backgrounds subtractions,T:

dimensionless correction factor of the TLD-100 between the calibration beam and the iodine-125 photons and the assumed the value was 1.4 for this expression [Abboud et. al., 2010; Reniers et. al., 2002], *d T* : a correction factor that explains the source decay during the TLD-100 irradiations and *Flin* represents a correction for non-linearity in TLD response and was assumed to be unity due to linear response in the doses (10 to 100 cGy) measured with

For the TLD-100 measurements a Harshaw 3500 TLD reader is used. The reader operates one dosimeter per load and with continuous flux of pure nitrogen (99,9995% of purity). Nitrogen fluxes are necessary to avoid the signals not delivered from the thermoluminescence dosimeter, as oxygen air induces signals. Heating rate of 10 oC.s-1 and maximum temperature of 260oC are the parameters of TLD-100 measurements used [Thermo Electron Corporation, 2002]. The measurements are performed 20 hours after the exposure; this delay

TLD-100 dosimeters demand thermal treatments to be reused. Theoretically, the thermal treatment will quench the dose information of previously irradiations. The thermal treatment

is dose rate ( 1 *cGy h* ) at any point with coordinates (, ) *r*

: calibration factor (nC.cGy-1) for each TLD-100, *E r* : a

, *Sk* : initial iodine-

structure were some parameters analyzed at the selection [Furreta and Weng, 1998].

Meigooni et. al., 2006; Abboud et. al., 2010].

from the dose levels (10 – 100 cGy).

where ( , ) *D r*

irradiation duration (h),

dose rates quantities the following formula is applied:

iodine brachytherapy seeds [Meigooni et. al., 2006].

is to avoid unstable glow peak which decays.

(, )

*D r R*

For adenocarcinoma of the prostate conventional treatment options that should be discussed with each patient in this category include radical prostatectomy, external beam radiation therapy, interstitial brachytherapy and watchful waiting, according to the NCI Consensus Conference in 1988 [Lee, 2003].

There are two types of prostate cancer radiation treatments: external and internal (interstitial). Brachytherapy is the interstitial one, meaning treatment is administered "within the tissue." External radiation therapy involves the projection of photon, electron, neutron, or proton beams into the prostate gland from a remote tool called the linear accelerator.

Ionizing radiation is used in the treatment of prostate cancer because exposure to this radiation damages the DNA of cells. Cells will not be damaged unless they attempt to divide. Cancerous cells divide more quickly than healthy cells. Therefore, healthy cells are able to repair damage before undergoing mitosis, while cancerous cells are not. Unfortunately, if the absorbed dose is strong enough, healthy cells will be damaged to the point where they cannot repair themselves before division. Interstitial brachytherapy is able to deliver higher doses of radiation to an area concentrated within the prostate gland [Van Dyk, 1999].

The use of brachytherapy as the sole modality of treatment for early-stage prostate cancer has gained popularity over the past decade due to the advent of the transrectal ultrasoundguided technique (TRUS) and the favorable reports of imaged-based brachytherapy with isotope Iodine-125 (I-125). At the same time, dose escalation 3-dimensional conformal radiation therapy (3D CRT) has revealed promising results, especially for patients with early stage disease [Halperin et. al., 2008].

#### **5.1 Brachytherapy process at the Albert Einstein hospital**

Initially the patient is referred to radiotherapy or search for a consultation with a radiation oncologist which defines the treatment plan in conjunction with the urologist involved in the process. The evaluation of radiotherapy will consist of complete history, complete physical examination including digital rectal examination, analysis of all imaging (transrectal ultrasound, computed tomography, magnetic resonance imaging, and / or chest radiography) and laboratory (complete blood count with coagulation, all measures of serum PSA). Additional investigations may be required to meet specific needs of each patient (diabetes, epilepsy, heart disease, renal disease, lung disease, etc). Therapeutic options, including observation, hormone therapy, radical prostatectomy, external beam radiotherapy or implantation of Iodine-125 seeds as well as acute and late side effects, expected or possible, are explained to the patient mainly by the urologist.

Theoretical, Manufacturing and Clinical

ureter in each section of the TRUS;

and quantity of seeds mCi.

et. al., 2004]; - The number of seeds;

1999].

Using system resources Variseed obtain:

second material (Surgical Center Medical Center-CCCM).

**5.4 Preparation of material for the implant**

each seeds using a well chamber (right).

**5.5 Standards for sterilization of seeds**

Place the test material (seed) in the sterilizer.

about 3 minutes ("flash").

Application Aspects of a Prostate Brachytherapy I-125 Source in Brazil 71

The team involved in the procedure of radiation therapy (medical, physical, and nursing assistants) handles the preparation of the material to be used in the procedure [Yu et. al.,

The charge physicist needs to control and verify the seeds that reach for each patient. It is recommended that the physicist verify at least 10% of the batch using a well chamber and the measure has a limit of 5% difference between the measured activity and the certificate The physicist is responsible for taking the seeds in magazines mounted to the center of the

 Fig. 6. Dosimetric verification of seeds for implant. Seed container (left). Measurement of

superimposed on the TRUS (transrectal ultrasound);

#### **5.2 Indication for brachytherapy**

The transperineal prostate implants guided by ultrasound is the most indicated and has a great potential to cure the patients diagnosed with prostate cancer with the following conditions:

For treatment alone:

Pre Planning and Ultrasound - The examination will be conducted with the equipment Leopard 2001 - B & K, using the ultrasonic transducer type 8558, coupled with the "Stepping Unit" UA1084. The "template" is B & K and the whole system is fixed to the stand Brachystand.

The exam aims to:

Identified clinically relevant changes in the query or ultrasound are discussed with other doctors responsible for feasibility of the procedure (heart disease, diabetes, clotting disorders, use of medications with potential interactions with the procedure used, calcifications, urethral defects, etc.).

#### **5.3 Drawing the boundary of the prostate**

In the planning system:

Using system resources Variseed obtain:

70 Brachytherapy

The transperineal prostate implants guided by ultrasound is the most indicated and has a great potential to cure the patients diagnosed with prostate cancer with the following

Intended dose: 90% of the target volume covered by the CT isodose 160Gy - (144Gy

Pre Planning and Ultrasound - The examination will be conducted with the equipment Leopard 2001 - B & K, using the ultrasonic transducer type 8558, coupled with the "Stepping Unit" UA1084. The "template" is B & K and the whole system is fixed to the stand Brachystand.

Gleason 6; (no individual values > 3; e.g. 2 +4 +2 or 4 will not be accepted);

according to recommendations of the TG 43) [Nath et. al., 1995]

pubic arch interference or micro macrocalcifications).

Identified clinically relevant changes in the query or ultrasound are discussed with other doctors responsible for feasibility of the procedure (heart disease, diabetes, clotting disorders, use of medications with potential interactions with the procedure used, calcifications, urethral

**5.2 Indication for brachytherapy**

Stage I or II (the T2aN0M0 T1C);

Fig. 5. Prostate volume determination.

**5.3 Drawing the boundary of the prostate**

defects, etc.).

In the planning system:

 Absence of prior transurethral resection (TUR) and Absence or small number of microcalcifications.

conditions:

For treatment alone:

The exam aims to:

 initial PSA 10 ng/ml; Prostate volume 45 grams;

#### **5.4 Preparation of material for the implant**

The team involved in the procedure of radiation therapy (medical, physical, and nursing assistants) handles the preparation of the material to be used in the procedure [Yu et. al., 1999].

The charge physicist needs to control and verify the seeds that reach for each patient. It is recommended that the physicist verify at least 10% of the batch using a well chamber and the measure has a limit of 5% difference between the measured activity and the certificate

The physicist is responsible for taking the seeds in magazines mounted to the center of the second material (Surgical Center Medical Center-CCCM).

Fig. 6. Dosimetric verification of seeds for implant. Seed container (left). Measurement of each seeds using a well chamber (right).

#### **5.5 Standards for sterilization of seeds**

Theoretical, Manufacturing and Clinical

from the anterior rectal wall mucosa.

ultrasound should be filled with seeds individually.

Fig. 7. Insertion of needles and seeds.

and 20% -25% in the center.

the needle by fluoroscopy.

**5.11 Placement of seeds**

**5.12 Cystoscopy**

seeds into the prostate.

Application Aspects of a Prostate Brachytherapy I-125 Source in Brazil 73

Realization of cystoscopy is performed by an urologist at the end of the introduction of

urethra. The typical number of needles in the central region is 3 to 5.

#### **5.6 Surgical Room procedures**

On the day of the procedure the patient is transferred to the operating room of the radiotherapy center through the nursing assistant of radiation therapy [Prestidge, 2008].

#### **5.7 Positioning the patient on the table**

The positioning of the patient on the operating table, and supine and lithotomy position with legs flexed according to the survey pre-planning.

#### **5.8 Anesthesia, monitoring and premedication**

The anesthesia may be Epidural, spinal or general. They vary according to the anesthesiologist responsible for assessment and multidisciplinary team member. Aabsolute immobility is essential. The timeis 2-3 hours for one procedure. We set up patient monitorings, and administrate prophylactic intravenous or perineal antibiotic treatment according to official regulation standateds established by Department of Anesthesia, and Office of Infection Control (SCIH), respectively. Saline via the urethral catheter is used to complete the volume, if necessary [Nath et. al., 2009].

#### **5.9 Images of the prostate via ultrasound**

#### **5.10 Insertion of needles and seeds**

#### **5.11 Placement of seeds**

72 Brachytherapy

On the day of the procedure the patient is transferred to the operating room of the radiotherapy center through the nursing assistant of radiation therapy [Prestidge, 2008].

The positioning of the patient on the operating table, and supine and lithotomy position

The anesthesia may be Epidural, spinal or general. They vary according to the anesthesiologist responsible for assessment and multidisciplinary team member. Aabsolute immobility is essential. The timeis 2-3 hours for one procedure. We set up patient monitorings, and administrate prophylactic intravenous or perineal antibiotic treatment according to official regulation standateds established by Department of Anesthesia, and Office of Infection Control (SCIH), respectively. Saline via the urethral catheter is used to complete the volume,

and activity of the seeds under the guidance of radiotherapist.

the urethra after 4 and 8 hours as stabilizers.

container that bear any responsible for sterilization.

possible.

**5.6 Surgical Room procedures**

if necessary [Nath et. al., 2009].

image as a template image.

**5.10 Insertion of needles and seeds**

**5.9 Images of the prostate via ultrasound**

**5.7 Positioning the patient on the table**

with legs flexed according to the survey pre-planning.

**5.8 Anesthesia, monitoring and premedication**

#### **5.12 Cystoscopy**

Realization of cystoscopy is performed by an urologist at the end of the introduction of seeds into the prostate.

Fig. 7. Insertion of needles and seeds.

Theoretical, Manufacturing and Clinical

**5.18 Dose volume analysis**

reported:

Application Aspects of a Prostate Brachytherapy I-125 Source in Brazil 75

The planning system facilitates structure-based analysis from axial image sets. This includes evaluation and analysis of isodose curves and generation of Dose-Volume Histograms (DVH). The calculation grid should be set no larger than (2 mm x 2 mm x the axial slice thickness). ABS and ESTRO Guidelines are available [Merrick et al., 2007]. DVH-based analysis must be completed in the post plan evaluation. The following values should be

Fig. 8. CT images in the 3D planning system and prostate histogram

#### **5.13 Radiometric survey of the room and the patient**

#### **5.14 X-ray control**

After the procedure the patient is referred Ximatron CX simulator for the performance of anterior-posterior radiographs and lateral-lateral control and for dosimetric calculations.

#### **5.15 Dose analysis**

A quantitative dose analysis must be carried out for each patient post implantation. This statement is based on the premise that it is as important to know and document the dose delivered by a permanent seed implant as by an external beam treatment. The importance of a post implant analysis cannot be overemphasized for the purposes of multi-: institutional comparison, improving techniques, evaluating outcome, and identifying patients who might benefit from supplemental therapy or be at risk for long-term morbidity [Yu et al., 1999].

#### **5.16 Brachytherapy dosimetry**

Calculations are performed in accordance with NIST 1999 calibration standards, the point source formalism described in by AAPM Task Group 43, and AAPM Subcommittee Reports [Nath et al., 1995; Rivard et al., 2004; Rivard et al., 2007].

#### **5.17 Prescribed dose**

The recommended prescription doses for Iodine-125 are 145 Gy and 110 Gy for monotherapy and boost implants, respectively. The prescription of minimum peripheral dose (mPD) is intended to cover the CTV, and is the reference dose for the treatment.

X-ray CT examination is performed immediately after implant and 3 to 5 weeks after. The patient is scanned in a supine position usually with bladder contrasting. Slices with thickness of 3 mm or less are acquired from 2 cm cephalad to the base of the gland to 2 cm caudad to the apex. All of the seeds used in the implant should be encompassed in the scan. ETVs (-Evaluation Treatment Volume) are determined from this scan, as the location of the urethra and the rectum. Due to the difficulty in CT visualization of the urethra, use of Foley catheterization is strongly recommended. The urethra and the rectum contours are drawn as the outer surface of the Foley catheter and the rectal wall, respectively. The CT images are used to create a post-implant treatment plan (post plan). An AP or anterior oblique pelvic radiograph is used to verify the number of sources and this will be recorded. A surview chest CT image is obtained to check any pulmonary migration of the source.

After the procedure the patient is referred Ximatron CX simulator for the performance of anterior-posterior radiographs and lateral-lateral control and for dosimetric calculations.

A quantitative dose analysis must be carried out for each patient post implantation. This statement is based on the premise that it is as important to know and document the dose delivered by a permanent seed implant as by an external beam treatment. The importance of a post implant analysis cannot be overemphasized for the purposes of multi-: institutional comparison, improving techniques, evaluating outcome, and identifying patients who might benefit from supplemental therapy or be at risk for long-term morbidity

Calculations are performed in accordance with NIST 1999 calibration standards, the point source formalism described in by AAPM Task Group 43, and AAPM Subcommittee Reports

The recommended prescription doses for Iodine-125 are 145 Gy and 110 Gy for monotherapy and boost implants, respectively. The prescription of minimum peripheral

X-ray CT examination is performed immediately after implant and 3 to 5 weeks after. The patient is scanned in a supine position usually with bladder contrasting. Slices with thickness of 3 mm or less are acquired from 2 cm cephalad to the base of the gland to 2 cm caudad to the apex. All of the seeds used in the implant should be encompassed in the scan. ETVs (-Evaluation Treatment Volume) are determined from this scan, as the location of the urethra and the rectum. Due to the difficulty in CT visualization of the urethra, use of Foley catheterization is strongly recommended. The urethra and the rectum contours are drawn as the outer surface of the Foley catheter and the rectal wall, respectively. The CT images are used to create a post-implant treatment plan (post plan). An AP or anterior oblique pelvic radiograph is used to verify the number of sources and this will be recorded. A surview

dose (mPD) is intended to cover the CTV, and is the reference dose for the treatment.

chest CT image is obtained to check any pulmonary migration of the source.

using the window opened because of the low energy iodine-125.

**5.13 Radiometric survey of the room and the patient**

initially loaded in magazines.

Nuclear Energy Commission.

**5.14 X-ray control**

**5.15 Dose analysis**

[Yu et al., 1999].

**5.17 Prescribed dose**

**5.16 Brachytherapy dosimetry**

[Nath et al., 1995; Rivard et al., 2004; Rivard et al., 2007].

Fig. 8. CT images in the 3D planning system and prostate histogram

#### **5.18 Dose volume analysis**

The planning system facilitates structure-based analysis from axial image sets. This includes evaluation and analysis of isodose curves and generation of Dose-Volume Histograms (DVH). The calculation grid should be set no larger than (2 mm x 2 mm x the axial slice thickness). ABS and ESTRO Guidelines are available [Merrick et al., 2007]. DVH-based analysis must be completed in the post plan evaluation. The following values should be reported:

Theoretical, Manufacturing and Clinical

Application Aspects of a Prostate Brachytherapy I-125 Source in Brazil 77

[14] Meigooni, A. S., Dini, S. A., Awan, S. B., Rafiq, Dou, K., Koona, R. A., 2006. Theoretical

[15] Merrick, G. S.; Zelefsky, M. J.; Sylvester, J.; Nag, S.; Bice, W. American brachytherapy

[16] Mobit, P., Badragan, I., 2003. Response of LiF-TLD micro-rods around 125I radioactive

[17] Moura, J.A.; Moura, E.S; Sprenger, F.E.; Nagatomi, H.R.; Zeituni, C.A.; Feher, A.;

[18] Nath, R., Meigooni, A. S., Meli, J. A., 1990. Dosimetry on transverse axes of 125I and

[19] Nath, R., Anderson, L.L., Luxton, G., Weaver, K.A., Williamson, J.F., Meigooni, A.S.,

[22] Oster, L., Horowitz, Y., Zlotopolsky, S., 2010. Investigation of the optical absorption charactheristics of slow-cooled LiF:Mg,Ti (TLD-100). Radiat. Meas. 45, 347-349. [23] Prestidge, B. R.; Amin, M.; Sanda, M.; Bruner, D. W.; Hartford, A.; Bice, W.; Michalski,

[25] Rivard, M. J., Coursey, B. M., DeWerd, L. A., Hanson, W. F., Huq, M. S., Ibbott, G. S.,

[26] Rivard, M. J., Butler, W. M., DeWerd, L. A., Huq, M. S., Ibbott, G. S., Meigooni, A. S.,

[28] Rostelato, M.E.C.M.; Rela, P. R.; Zeituni, C.A.; Feher, A.; Manzoli, J.E.; Moura, J.A.;

during the leak test of iodine-125 seeds. Nukleonika; 55(3):409-413.

192Ir interstitial brachytherapy sources. Med. Phys. 17, 1032-1040.

Manzoli, J.E.; Souza, C.D.; Rostelato, M.E.C.M.; (2010) Tubing decontamination

1995b. Dosimetry of interstitial brachytherapy sources: recommendations of the AAPM Radiation Therapy Committee Task Group No. 43. Med. Phys. 22, 209-234. [20] Nath, R., Yue, N., 2002. Dosimetric characterization of an encapsulated interstitial brachytherapy source of 125I on a tungsten substrate. Brachytherapy 1, 102-109. [21] Nath, R.; Bice, W. S.; Butler, W. M.; Chen, Z.; Meigooni, A. S. Narayana, V.; Rivard, M.

J.; Yu, Y. AAPM recommendations on dose prescription and reporting methods for permanent interstitial brachytherapy for prostate cancer: Reportof Task Group 137.

J.; Ibbot, G. A phase III study comparing combined external beam radiation and transperineal interstitial permanent brachytherapy with brachytherapy alone for selected patients with intermediate risk prostatic carcinoma (RTOG-0232). Radiation Therapy Oncology Group (RTOG 0232), MD Anderson Center, 2008. [24] Reniers, B., Vynckier, S., Scalliet, P., 2002. Dosimetric study of a new palladium seed.

Mitch, M. G., Nath, R., Williamson, J. F., 2004. Update of AAPM Task Group No. 43 Report: A revised AAPM protocol for brachytherapy dose calculations. Med. Phys.

Melhus, C. S., Mitch, M. G., Nath, R., Williamson, J. F., 2007. Supplement to the 2004 update of the AAPM Task Group No. 43 Report. Med. Phys. 34, 2187-2205. [27] Rostelato, M. E. C. M., 2006. Estudo e Desenvolvimento de uma nova Metodologia para

Confecção de Sementes de Iodo-125 para Aplicação em Braquiterapia. Ph. D.

Moura, E.S.; Silva, C.P.G. (2008) Development and production of radioactive sources used for cancer treatment in Brazil. Nukleonika; 53(Supplement 2):S99-S103

THINSeedTM brachytherapy source. Med. Phys. 37, 1681-1688.

society prostate low-dose rate task group. ABS, 2007.

seed. Phys. Med. Biol. 48, 3129-3142.

Med. Phys. 36 (11), 2009.

Appl. Radiat. Isot. 57, 805-811.

Thesis, University of São Paulo.

31, 633-674

and experimental determination of dosimetric characteristics for ADVANTAGETM Pd-103 brachytherapy source. Appl. Radiat. Isot. 64, 881–887. 14 – Kennedy, R. M., Davis, S. D., Micka, J. A., DeWerd, L. A., 2010. Experimental and Monte Carlo determination of the TG-43 dosimetric parameters for the model 9011

where Vn is the percentage of the ETV that received at least n% of the prescription dose. Dm is the minimum dose received by m% of the ETV. [Merrick et. al., 2007]:

The maximum dose to the rectum and the volume of the rectum (cm3) that was received more than 100% of the prescription dose.

#### **6. References**

The maximum dose to the rectum and the volume of the rectum (cm3) that was received

[1] Abboud, F., Hollows, M., Scalliet, P., Vynckier, S., 2010. Experimental and theoretical

[2] Baltas, D.; Sakelliou, L.; Zamboglou, N (2006). The physics of modern brachytherapy for oncology. CRC Press Taylor & Francis Group, ISBN-10:<PHONE_NUMBER>, FL/USA [3] Burns, G. S., Raeside, D. E., 1987. Monte Carlo simulation of the dose distribution around

[4] Chiu-Tsao, S., Anderson, L. L., O'Brien, K., Sanna, R., 1990. Dose rate determination for

[5] Cieszykowska, I.; Piasecki, A.; Mielcarski, M. (2005) An approach to the preparation of

[6] Furreta, C., Weng, P., 1998. Operational Thermoluminescence Dosimetry. Singapore:

[7] Halperin, E. C.; Perez, C. A.; Brady, L.W. (Ed.). Perez and Brady's Principles and Practice of Radiation Oncology. 5. ed. Baltimore: Lippincott Williams & Wilkins, 2008. [8] Han, H.S.; Park, Ui-J., Son, K.J.; Lee, J.S.; Hong, S.B.; Ham, S.S (2007) Development of

[9] INTERNATIONAL STANDARD ORGANIZATION. Radiation protection Sealed

[10] Lee, R. W. A phase II study of external beam radiation therapy combined with

[11] Mathew, C.; Majali, M.A.; Balakrishnan, S.A. (2002) A novel approach for the

[12] Meigooni, A. S., Meli, J. A., Nath, R., 1988. A comparison of solid phantoms with water for dosimetry of 125I brachytherapy sources. Med. Phys. 15, 695-701. [13] Meigooni, A. S., Yoe-Sein, M. M., Al-Otoom, A. Y., Sowards, K. T., 2002. Determination

treatment of eye and prostate cancer. Appl Radiat Isot 57:359–367

production technology of 125I seed for brachytherapy. J Label Compd Radiopharm;

radioactive sources – General requirements and classification. Mar. 08, 1995. (ISO-

permanent source brachytherapy for intermediate risk clinically localized adenocarcinoma of the prostate (RTOG P-0019). Radiation Therapy Oncology

adsorption of iodine-125 on silver wire as matrix for brachytherapy source for the

of the dosimetric characteristics of InterSource 125Iodine brachytherapy source.

Dosimetric impact of fluorescence x rays. Med. Phys. 37, 2054-2062.

dosimetry of a new polymer encapsulated iodine-125 source-SmartSeed:

more than 100% of the prescription dose.

125I seeds. Med. Phys. 14, 420-424.

125I seeds. Med. Phys. 17, 815-825.

50: 321–322

2919)

World Scientific Publishing Co, pp. 127.

iodine-125 seed-type source. Nukleonika 50;1:17–22

Group (RTOG P-0019), MD Anderson Center, 2003.

Appl. Radiat. Isot. 56, 589-599.

more than 200% of the prescription dose [U200 (cm3)].

is the minimum dose received by m% of the ETV. [Merrick et. al., 2007]:

**6. References**

**5**

**High Dose Rate Endobronchial**

**Brachytherapy in Lung Cancer**

Alejandro B. Santini1, Benjamín G. Bianchi1,

*1National Cancer Institute (INC), Santiago, 2National Thorax Institute (INT), Santiago,*

*3Los Andes University*

*1,2Chile 3Colombia*

**in Patients with Central Airway Obstruction**

The term brachytherapy derives from the Greek "brachys", which means "short" or "close". It is the branch of radiotherapy in which the radioactive source is located near the therapeutic target. The reported first use of endobronchial brachytherapy (EBBT) done by Yankauer in 19921,. He inserted Radon seeds directly into lung tumors though a rigid

Recent technological development of brachytherapy equipment with small and high dose rate sources, clinical application of EBBT became safe, fast, remote, precise, and less invasive (Fig 1), expanding its indication and feasibility in symptomatic palliation and curative

One of the major role of EBBT is palliation of symptoms caused by endobronchial cancer ingrowth. Boost EBBT to endobronchial gross tumors combined with external beam radiotherapy (EBRT) provides not only palliative but curative possibilities2. In small endobronchial tumors EBBT is used as definitive curative treatment3.EBBT is also used for non-oncologic pathologies4,5. The majority of non-small cell lung cancer (NSCLC)found at loco-regionally advanced stage and frequently associated with bronchial obstruction Various endoscopic techniques available today are including cryotherapy, stent, laser, photodynamic, and EBBT6,7. Among these EBBT in the only one that provides biologically

The National Institute for Cancer in Santiago, Chile (Instituto Nacional del Cáncer de Santiago de Chile) has had EBBT HDR since October 2004, and began treating patients in March 2006, along with the Bronchoscopy department in Chest National Institute. The purpose of this work is to analyze of the result obtained in our center in the palliation of

symptoms related to the tumor obstruction of the airway, and literature review.

tumoricidal effect keeping the normal tissue structure as is.

**1. Introduction**

bronchoscope.

treatment.

Dionis D. Isamitt2, Claudia C. Carvajal3 and Gonzalo P. Silva3

## **High Dose Rate Endobronchial Brachytherapy in Lung Cancer in Patients with Central Airway Obstruction**

Alejandro B. Santini1, Benjamín G. Bianchi1, Dionis D. Isamitt2, Claudia C. Carvajal3 and Gonzalo P. Silva3 *1National Cancer Institute (INC), Santiago, 2National Thorax Institute (INT), Santiago, 3Los Andes University 1,2Chile 3Colombia*

#### **1. Introduction**

78 Brachytherapy

[29] Seltzer, S. M., Lamperti, P. J., Loevinger, R., Mitch, M. G., Weaver, J. T., Coursey, B. M.,

[31] Thomson, R. M., Rogers, D. W. O., Monte Carlo dosimetry for 125I and 103Pd eye plaque brachytherapy with various see models. Med. Phys. 37, 368-376. [32] Usher-Moga, J., Beach, S. M., DeWerd, L. A., 2008. Spectroscopic output of 125I and 103Pd low dose rate brachytherapy sources. Med. Phys. 36, 270-278. [33] Van Dyk, J. (Ed.). The modern technology of radiation oncology – A compendium for

[34] Wallace, R. E., Empirical dosimetric characterization of model I125-SL 125Iodine

[35] Yu, Y.; Anderson, L.L. Li, Z.; Mellenberg, D. E.; Nath, R.; Schell, M. C.; Waterman, F. M.;

[36] Zeituni, C. A., 2008. Dosimetria de fontes de iodo-125 aplicadas em braquiterapia. Ph.

[37] Zeituni, C.A.; Rostelato, M.E.C.M.; Son, K.J.; Lee, J.S.; Costa, O.L.; Moura, J.A.; Feher,

Brachytherapy Seeds. J. Res. Natl. Inst. Stand. Technol. 108, 337-358. [30] Thermo Electron Corporation, 2002. Harshaw Standard TTP Recommendations

Technical Notice. Publication Number: DOSM-0-N-1202-001.

brachytherapy source in phantom. Med. Phys. 27, 2796-2802.

1999.

(10), 1999.

D. Thesis, University of São Paulo.

Technologies – NUTECH-2011.

2003. New National Air-Kerma-Strength Standards for 125I and 103Pd

medical physicists and radiation oncologists. Madison: Medical Physics Publishing,

Wu, A.; Blasko, J. C. Permanent prostate seed implant brachytherapy: Report of the American Association of Physicists in Medicine Task Group No. 64. Med. Phys. 26

A.;Moura, E.S.; Souza; C.D.; Mattos, F.R.; Peleias Jr., F.S.; Karam Jr., D. (2011) Production of iodine-125 in nuclear reactors: advantages and disadvantages of production in batch or continuous production in cryogenic system. Proceedings of International Conference on Developments and Applications of Nuclear

The term brachytherapy derives from the Greek "brachys", which means "short" or "close". It is the branch of radiotherapy in which the radioactive source is located near the therapeutic target. The reported first use of endobronchial brachytherapy (EBBT) done by Yankauer in 19921,. He inserted Radon seeds directly into lung tumors though a rigid bronchoscope.

Recent technological development of brachytherapy equipment with small and high dose rate sources, clinical application of EBBT became safe, fast, remote, precise, and less invasive (Fig 1), expanding its indication and feasibility in symptomatic palliation and curative treatment.

One of the major role of EBBT is palliation of symptoms caused by endobronchial cancer ingrowth. Boost EBBT to endobronchial gross tumors combined with external beam radiotherapy (EBRT) provides not only palliative but curative possibilities2. In small endobronchial tumors EBBT is used as definitive curative treatment3.EBBT is also used for non-oncologic pathologies4,5. The majority of non-small cell lung cancer (NSCLC)found at loco-regionally advanced stage and frequently associated with bronchial obstruction Various endoscopic techniques available today are including cryotherapy, stent, laser, photodynamic, and EBBT6,7. Among these EBBT in the only one that provides biologically tumoricidal effect keeping the normal tissue structure as is.

The National Institute for Cancer in Santiago, Chile (Instituto Nacional del Cáncer de Santiago de Chile) has had EBBT HDR since October 2004, and began treating patients in March 2006, along with the Bronchoscopy department in Chest National Institute. The purpose of this work is to analyze of the result obtained in our center in the palliation of symptoms related to the tumor obstruction of the airway, and literature review.

High Dose Rate Endobronchial Brachytherapy

**Grade Description**

0 Without dyspnea

3 Dyspnea in rest 4 Requires oxygen

0 Without cough

1 Dyspnea in moderate effort 2 Dyspnea in normal activity

1 Intermittent, no medication required

4 Constant, not improved with narcotics

2 More than twice a week, but less an everyday

than 2 U of red blood cells.

4 Hemoglobin decreases and/or hematocrit in more than 10% or more

Table 1. Sympton's scale of American Brachytherapy Society (Speiser and Spratling)

than 150 ml. Requires to be admitted in hospital or transfusion of more

2 Intermittent, no narcotics required

3 Constant, narcotics required

0 Without hemoptisis

1 Less than twice a week

3 Daily, red bright blood or clot

Dyspnea

Cough

Hemoptysis

in Lung Cancer in Patients with Central Airway Obstruction 81

was transferred to are mote high loading dose (iridium-192 source) brachytherapy equipment (VariSource iX, Varian Medical Systems). We prescribed 1 to 4 fractions of 7 to 7.5 Gy (range of total, 7 – 30Gy )at 1 cm depth point from the endobronchial surfacecovering the macroscopic lesion with a safety margin of additional 1 cm (Figure 2). The fractional interval between brachytherapy session was 1 week. In patients with significant or complete bronchial obstruction, we applied electrofulguration before installing the catheter, or installed the catheter through the tumor stenosis/obstruction into the peripheral end. Both the catheter installation procedure by BFC and HDR-EBBT were performed in an outpatient setting. Patients were followed up and evaluated for effect and complications at

next week of the last brachytherapy session and at the second month. .

Fig. 1. Varisourse Brachytherapy equipment (patient with a catheter in airway during treatment)

#### **2. Patients, materials and methods**

From March 2006 to November 2009, 27 patients were treated with 82 HDR-EBBT procedures as palliative treatment for advanced cancer.

The indication criteria for included: Being able to tolerate decubitus supine position that allows fiberrbronchoscopy examination(FBC), there were clear evidence of tumors with intraluminal component (with or without extrabronchial component), life expectancy of over 3 months, no immediately life-threatening airway obstruction , and healthy coagulating condition. All patients were clinically assessed and the symptoms were evaluated according to Speiser and Spratling8, recommended by American Brachytherapy Society (ABS), (table 1), prior to and one week after the end of the treatment.

Premedication including included sedatives, and local endobronchial anesthesia which were commonly used in usual FBC.

We used two equipment:

During FBC, the physician evaluated the percentage of luminal obstruction of the air way (table 2), repeating these evaluations after the following FBC.

At the first FBC, the extension of the lesion was measured: the anatomic potion of thee carina was used as reference point to measure lesion extension towards cranium or caudal. After confirmation of the precise target location that was recognized as clearly limited or demarcated, one or two endobronchial brachytherapy applicator catheters (Varian (metaltipped 4.7, FR-150 cm long (PTFE) R)) were installed ,, with a radiopaque terminal that keeps its position by means of nasal fixing. After insertion of the catheter, or in advance, we used of codeine for managing cough caused by the dwelling catheters in the airway.

The HDR-EBBT planning was simulated on computer associated tomography (CAT) images. using planning computer ( Brachyvision system , Varian Medical Systems), which

Fig. 1. Varisourse Brachytherapy equipment (patient with a catheter in airway during

From March 2006 to November 2009, 27 patients were treated with 82 HDR-EBBT

The indication criteria for included: Being able to tolerate decubitus supine position that allows fiberrbronchoscopy examination(FBC), there were clear evidence of tumors with intraluminal component (with or without extrabronchial component), life expectancy of over 3 months, no immediately life-threatening airway obstruction , and healthy coagulating condition. All patients were clinically assessed and the symptoms were evaluated according to Speiser and Spratling8, recommended by American Brachytherapy Society (ABS), (table

Premedication including included sedatives, and local endobronchial anesthesia which were

a. Video bronchoscope Fujinon, model EB-270S working channel of 2.0 mm, flexible tube

b. Fibrobronchoscope Olympus, model BF-TE2 working channel of 2.8mm, flexible tube of

During FBC, the physician evaluated the percentage of luminal obstruction of the air way

At the first FBC, the extension of the lesion was measured: the anatomic potion of thee carina was used as reference point to measure lesion extension towards cranium or caudal. After confirmation of the precise target location that was recognized as clearly limited or demarcated, one or two endobronchial brachytherapy applicator catheters (Varian (metaltipped 4.7, FR-150 cm long (PTFE) R)) were installed ,, with a radiopaque terminal that keeps its position by means of nasal fixing. After insertion of the catheter, or in advance, we

The HDR-EBBT planning was simulated on computer associated tomography (CAT) images. using planning computer ( Brachyvision system , Varian Medical Systems), which

used of codeine for managing cough caused by the dwelling catheters in the airway.

treatment)

**2. Patients, materials and methods**

commonly used in usual FBC.

of 4.9 mm in diameter.

4.9 mm in diameter.

We used two equipment:

procedures as palliative treatment for advanced cancer.

1), prior to and one week after the end of the treatment.

(table 2), repeating these evaluations after the following FBC.

was transferred to are mote high loading dose (iridium-192 source) brachytherapy equipment (VariSource iX, Varian Medical Systems). We prescribed 1 to 4 fractions of 7 to 7.5 Gy (range of total, 7 – 30Gy )at 1 cm depth point from the endobronchial surfacecovering the macroscopic lesion with a safety margin of additional 1 cm (Figure 2). The fractional interval between brachytherapy session was 1 week. In patients with significant or complete bronchial obstruction, we applied electrofulguration before installing the catheter, or installed the catheter through the tumor stenosis/obstruction into the peripheral end. Both the catheter installation procedure by BFC and HDR-EBBT were performed in an outpatient setting. Patients were followed up and evaluated for effect and complications at next week of the last brachytherapy session and at the second month. .

Table 1. Sympton's scale of American Brachytherapy Society (Speiser and Spratling)

High Dose Rate Endobronchial Brachytherapy

Age (years)

Diagnosis

Cancer Histology

Cancer Stages

Location

Sex

in Lung Cancer in Patients with Central Airway Obstruction 83

**Variables Number (%)**

Mean ± standard deviation 63,07 ± 12,95

Male 15 (56%) Female 12 (47%)

Lung Cancer 21(78%) Amyloidosis 1 (3%) Esophageal Cancer 1 (3%) Renal cancer 3 (12%) Bronchial carcinoid 1 (3%)

Adenocarcinoma 10 (37%) Epidermoid 11 (40%) Undifferentiated NSCLC 1 (3%) Bronchial carcinoid 1 (3%) CP large cell 1 (3%) Small cell CP 1 (3%)

IIIA 1 (4%) IIIB 7 (28%) IV 16 (64%) Relapses 1 (4%)

Right bronchus 18 (66%) Left bronchus 11 (40%) Carina 14 (51%) Trachea 4 (14%) Palliative external beam radiotherapy (overprint) 8 (30%)

Most of the patients had more than one location.

endobronchial brachytherapy high doses (HDR-EBBT)

Total number of staged patinets is 26 because eliminating a patients with benign concurrent disease.

Table 3. This table summarizes the characteristics of the 27 patients who underwent

Table 2. Grade of obstruction

#### **3. Results**

Patient consisted of 15 men and 12 women and their age ranged 32-85 years old. The most frequent histologic cancer type was NSCLC, with the main subtype being squamous carcinoma (40%). 7 patients (26%) were previously treated with palliative radiotherapy:(5 patients received 40 Gy in 20 fractions, one received 30 Gy in 10 fractions, one 20 Gy in 5 fractions and the other one 8 Gy in 1 fraction.. At the time of EBBT no patients were receiving concomitant chemotherapy, while a few received chemotherapy previously for relapsed tumor. Table 3 summarizes the characteristics of the 27 patients who received HDR-EBBT.

Lesion location, extent and degree of airway obstruction are described in Table 3 and Figure 3.

With this treatment, a significant improvement was observed in every evaluated symptom (hemoptysis, cough, dyspnea and obstruction). Table 4 compares symptomatic scores before and 1 week after treatment. One patient did not complete treatment for personal reasons, and another one died secondary to a hemorragic complication from the contralateral bronchial tree. Thus 25 patients were evaluable for dyspnea, hemoptysis and cough. 22 patients underwent bronchoscopic reevaluation for degree of obstruction after treatment: One patient with significant clinical improvement refused the reevaluation.

Fig. 2. Dose distribution of a treatment planning to main left bronchus lesion causing left superior lobar atelectasis. Thick green line: catheter in treatment position: Cayn clouered contur between red and yellow indicates 100% of the prescribed dose .

Patient consisted of 15 men and 12 women and their age ranged 32-85 years old. The most frequent histologic cancer type was NSCLC, with the main subtype being squamous carcinoma (40%). 7 patients (26%) were previously treated with palliative radiotherapy:(5 patients received 40 Gy in 20 fractions, one received 30 Gy in 10 fractions, one 20 Gy in 5 fractions and the other one 8 Gy in 1 fraction.. At the time of EBBT no patients were receiving concomitant chemotherapy, while a few received chemotherapy previously for relapsed tumor. Table 3 summarizes the characteristics of the 27 patients who received

Lesion location, extent and degree of airway obstruction are described in Table 3 and Figure 3. With this treatment, a significant improvement was observed in every evaluated symptom (hemoptysis, cough, dyspnea and obstruction). Table 4 compares symptomatic scores before and 1 week after treatment. One patient did not complete treatment for personal reasons, and another one died secondary to a hemorragic complication from the contralateral bronchial tree. Thus 25 patients were evaluable for dyspnea, hemoptysis and cough. 22 patients underwent bronchoscopic reevaluation for degree of obstruction after treatment:

Fig. 2. Dose distribution of a treatment planning to main left bronchus lesion causing left superior lobar atelectasis. Thick green line: catheter in treatment position: Cayn clouered

contur between red and yellow indicates 100% of the prescribed dose .

One patient with significant clinical improvement refused the reevaluation.

**Grades Obstruction**

G4 Full obstruction Table 2. Grade of obstruction

**3. Results**

HDR-EBBT.

G0 Without evidences of obstruction

G2 Obstruction between 25-75%

G3 Obstruction more than 75%

G1 Equivalent or less than 25% of obstruction

Total number of staged patinets is 26 because eliminating a patients with benign concurrent disease. Most of the patients had more than one location.

Table 3. This table summarizes the characteristics of the 27 patients who underwent endobronchial brachytherapy high doses (HDR-EBBT)

High Dose Rate Endobronchial Brachytherapy

brachytherapy in several nations16.

**4. Discussion**

argon plasma17. *EBBT Indications*

techniques6, 18.19.

**1. Palliative treatment**

in Lung Cancer in Patients with Central Airway Obstruction 85

The HDR-EBBT provides rapid and significant symptomatic improvement of related to main airway obstruction when the selection of patients is adequate. Our results are consistent with that reported previously (Table 5). These excellent results, with the progress in radioisotope security issue and the outpatient treatment possibility owing to recent decade's technological advances, have made EBBT one of the major applications of

Currently, EBBT is a part of the therapeutic arsenal in interventional bronchoscopy, being complementary to other techniques such as cryotherapy, laser, photodynamic, stents and

There are several comprehensive publications that develop the indications and treatments

According to the recommendations of the ABS (American Brachytherapy Society)18 and the ESTRO (European Society of Therapeutic Radiology and Oncology)19 indications could be

Patients with large endobronchial tumors which cause symptoms such as dyspnea due to obstruction, cough, bleeding, or post obstructive pneumonia, represent the most common EBBT indication. Contrary, those tumors that cause obstruction mainly due to extrinsic airway compression would not be candidates for this treatment. Patients with critical obstruction and airway compromise are not recommended for exclusive use of this technique, but it can be used after initial treatment with laser, cryotherapy, stents or

According to Nag18, the EBBT might be more effective than a two or three weeks treatment with external beam radiotherapy (EBRT), indicated at first instance, in patients with life expectancy greater than three months that are not candidates for surgery or EBRT due to poor lung function after radiation therapy. Kelly et al, from MD Anderson, discussed their 10 years' experience with EBBT11. These authors treated a group of patients with the worst prognosis. Given that, two thirds had already received palliative EBRT. However, they got a 66% improvement of symptoms. Escobar-Sacristán et al, from the Military Hospital of Madrid, reported 85 patients with symptomatic advanced lung cancer who received 288 EBBT applications with 85% partial improvement in symptoms (cough, dyspnea,

electrocautery20, 21 with great results and ostensible improvement in quality of life.

hemoptysis, and obstruction) and 60% complete responses using endoscopic EBBT22.

according to the linear quadratic model23, and the results are very similar,7,13,24-26.

The treatment schedule, i.e., the dose and the number of applications vary in different sites and authors as shown in Table 5. When treatment is performed exclusively, most publications have suggested dose and fractionation schemes between 15 and 35 Gy in one to five applications, calculated within 1 cm from the source. However, more recent studies recommended not exceeding 30 Gy with EBBT19. The ABS recommends 3 fractions of 7.5 Gy, two of 10 Gy or four of 6 Gy. These fractions have the same radiobiological equivalent

divided into: Palliative treatment, healing and non-oncologic pathology.

Table 4. Patient symptoms according to the Speiser-Spratling scale before and after HDR-EBBT

Symptomatic improvement was observed in all hemoptysis condition, 40% of dyspnea, and 25% coughing condition after treatment. After treatment, no patient had G3 or G4 symptoms.

The EBBT procedure was well tolerated, with no acute complications registered. Two months after treatment, two patients (7%) had significant hemoptysis and bronchoscopic examination revealed these bleeding were originated from different locations.. One patient discontinued treatment because of personal choice.

The average treated volume (100% isodose) was 38.1 cm3(SD 15.4)(this shows the smallness of the irradiated tissue volume with this technique)

### **4. Discussion**

84 Brachytherapy

Dyspnea G0 3 (11,1%) 10 (37%)

Hemoptysis G0 4 (14,8%) 25 (92,6%)

Obstruction G0 1 (3,7%) 9 (33,3%)

Cough G0 3 (11,1%) 9 (33,3%)

**Prior to the EBBT n patients (%)**

G1 2 (7,4%) 13 (48,1%) G2 13 (48,1%) 2 (7,4%)

G3 8 (29,6%) 0 G4 1 (3,7%) 0

G1 3 (11,1) 0 G2 9 (33,3%) 0 G3 11 (40,1%) 0

G4 0 0

G3 8 (29,6%) 0

G4 3 (11,1%) 0

G3 13 (48,1%) 0 G4 0 0

Table 4. Patient symptoms according to the Speiser-Spratling scale before and after HDR-

Symptomatic improvement was observed in all hemoptysis condition, 40% of dyspnea, and 25% coughing condition after treatment. After treatment, no patient had G3 or G4

The EBBT procedure was well tolerated, with no acute complications registered. Two months after treatment, two patients (7%) had significant hemoptysis and bronchoscopic examination revealed these bleeding were originated from different locations.. One patient

The average treated volume (100% isodose) was 38.1 cm3(SD 15.4)(this shows the

discontinued treatment because of personal choice.

smallness of the irradiated tissue volume with this technique)

G1 4 (14,8%) 12 (44,4%) G2 11 (40,07%) 1 (3,7%)

G1 2 (7,4%) 13 (48,1%)

G2 9 (33,3%) 3 (11,1%)

**Post to the EBBT n°**

**patients (%)**

**Variable Degree of**

EBBT

symptoms.

**symptoms**

The HDR-EBBT provides rapid and significant symptomatic improvement of related to main airway obstruction when the selection of patients is adequate. Our results are consistent with that reported previously (Table 5). These excellent results, with the progress in radioisotope security issue and the outpatient treatment possibility owing to recent decade's technological advances, have made EBBT one of the major applications of brachytherapy in several nations16.

Currently, EBBT is a part of the therapeutic arsenal in interventional bronchoscopy, being complementary to other techniques such as cryotherapy, laser, photodynamic, stents and argon plasma17.

#### *EBBT Indications*

There are several comprehensive publications that develop the indications and treatments techniques6, 18.19.

According to the recommendations of the ABS (American Brachytherapy Society)18 and the ESTRO (European Society of Therapeutic Radiology and Oncology)19 indications could be divided into: Palliative treatment, healing and non-oncologic pathology.

#### **1. Palliative treatment**

Patients with large endobronchial tumors which cause symptoms such as dyspnea due to obstruction, cough, bleeding, or post obstructive pneumonia, represent the most common EBBT indication. Contrary, those tumors that cause obstruction mainly due to extrinsic airway compression would not be candidates for this treatment. Patients with critical obstruction and airway compromise are not recommended for exclusive use of this technique, but it can be used after initial treatment with laser, cryotherapy, stents or electrocautery20, 21 with great results and ostensible improvement in quality of life.

According to Nag18, the EBBT might be more effective than a two or three weeks treatment with external beam radiotherapy (EBRT), indicated at first instance, in patients with life expectancy greater than three months that are not candidates for surgery or EBRT due to poor lung function after radiation therapy. Kelly et al, from MD Anderson, discussed their 10 years' experience with EBBT11. These authors treated a group of patients with the worst prognosis. Given that, two thirds had already received palliative EBRT. However, they got a 66% improvement of symptoms. Escobar-Sacristán et al, from the Military Hospital of Madrid, reported 85 patients with symptomatic advanced lung cancer who received 288 EBBT applications with 85% partial improvement in symptoms (cough, dyspnea, hemoptysis, and obstruction) and 60% complete responses using endoscopic EBBT22.

The treatment schedule, i.e., the dose and the number of applications vary in different sites and authors as shown in Table 5. When treatment is performed exclusively, most publications have suggested dose and fractionation schemes between 15 and 35 Gy in one to five applications, calculated within 1 cm from the source. However, more recent studies recommended not exceeding 30 Gy with EBBT19. The ABS recommends 3 fractions of 7.5 Gy, two of 10 Gy or four of 6 Gy. These fractions have the same radiobiological equivalent according to the linear quadratic model23, and the results are very similar,7,13,24-26.

High Dose Rate Endobronchial Brachytherapy

respectively)28.

**5. Conclusion**

**6. References**

1922;115:741-742

1605 - 1610.

2006;28;200-18

Radiat Oncol Biol Phys 2000:47(3):665-672

obstruction in 2008 patient CHEST 1996:110.1536-42

afteroading technique in 365 patients. Lung 1999;173:274-80

in Lung Cancer in Patients with Central Airway Obstruction 87

boost or overlay to EBRT compared to exclusively use of EBRT (58 versus 32% at 5 years,

We understand that the EBRT is preferred as a palliative treatment when the airway compression is extrinsic, when EBBT is not indicated. In patients with tumors, with an intrinsic component in the airway lumen, Kelly and colleagues from MD Anderson, say that

The HDR-EBBT is a useful technique in the symptomatic treatment of ambulatory patients with central airway obstruction. The procedure is well tolerated and effective with low complications rate. Main indications are patients with advanced lung cancer, where the objective is only palliative. It must also be considered in situations of incipient tumors for patients with contraindications for surgery or EBRT, boosted after a first treatment with

[1] Yankauer S. Two cases of lung tumour treated bronchoscopically. NY Med J

[2] Hennequin C, Bleichiner O, Trédaniel J y col. Long term results of endobronchial

[3] Marsiglia H, Baldeyrou P, Larigau E, Brioth E, Haie C, Le chevalier L y col. High Dose

[4] Kramer MR, Kats A, Yarmolowsky A y col. Successful use of high dose rate brachytherapy for non-malignant bronchial obstruction. Thorax 2001;56:415-416 [5] Brenner, M. R. Kramer, A. Katz, R. Feinmesser, y col. High Dose Rate Brachytherapy for

[6] Vergnon JM, Huber RM and Moghissi K. Place of cryotherapy, brachytherapy and

[7] Cavaliere S, Ventura F, Foccoli P y col. Endoscopic treatment of malignant airway

[8] Speiser BL, Sparting L. Remote afterloading brachytherapy for local control of endobronchyal carcinoma. Int J Radiat Oncol Biol Phys 1993;25:579-87 [9] Macha HN, Wahlers B, Reichle C y col. Endobronchial radiation therapy for obstructing

[10] Muto P, Ravo V, Pannelli C y col. High-Dose-rate brachytherapy of bronchial cancer:

[11] Kelly J, Delclos M, Morice R Y col. High-Dose.rate Endobroncial Brachytherapy

brachhytherapy: a Curative treatment? Int J radiat Oncol Biol Phys 2007;67(2);425-30.

Rate Brachytherapy as sole Modality for early stage Endobronchial carcinoma. In J

Nonmalignant Airway Obstruction: New Treatment Option. Chest, 2003; 124(4):

photodynamic therapy in therapeutic bronchoscopy of lung cancers. Eur Eespir J

malignancies. Ten years experience with IR192 hiagh-Dose-radiation Brach therapy

treatment optimization using thee schemes of therapy. The Oncology 2000;5:209-14

afterloading palliative symptoms due to airway tumor. The ten years MD Anderson Cancer Center experience Int J Radiat Oncol Biol Phys 2000;48(3):697-702

one of the advantages of HDR-EBBT would be the shorter treatment time11.

EBRT or in benign disease with endobronchial or endotracheal scar proliferation.

Table 5. Published results of HDR endobronchial brachytherapy as palliative treatment

#### **2. Curative treatment**

EBBT has been used in curative treatment of lung cancer, both in the exclusive treatment of early tumors with EBRT as overprint (boost or reirradiation)2, 3. About the first indication, Marsiglia et al, reported a two year survival rate of 78% in 34 patients with small tumors without evidence of spread that were treated only with HDR-EBBT with a 30 Gy dose in 6 fractions3.Hennequin et al, in a series of 106 patients with localized tumors that were not candidates for surgery or EBRT, obtained a specific 3 and 5 years survival of 60% and 50% respectively2.The ABS recommended a healing (palliative) dose is 3 fractions of 5 to 7.5 Gy (total 15 – 22.5Gy) when the patient already received 60 Gy pretreatment with EBRT, and 5 to 6 fractions of 5 to 7 Gy (total 25 – 42 Gy) if this treatment is exclusively used 17.

#### **3. Non-oncologic pathology treatment**

Several authors have published interesting experiences regarding the use of EBBT in nonmalignant pathology. This treatment modality has been used successfully in patients with granulomatous proliferation after metal stent placement because of non-malignant airway stenosis, or pulmonary transplant patients4,5.

In patients who have not received EBRT it is feasible to use the combination of EBBT and EBRT in order to improve results. In a randomized study, the combination of those treatments proved to be more effective than single-EBRT in symptomatic improvement27. Mantz and colleagues, obtained a significant increase in local control when using a EBBT boost or overlay to EBRT compared to exclusively use of EBRT (58 versus 32% at 5 years, respectively)28.

We understand that the EBRT is preferred as a palliative treatment when the airway compression is extrinsic, when EBBT is not indicated. In patients with tumors, with an intrinsic component in the airway lumen, Kelly and colleagues from MD Anderson, say that one of the advantages of HDR-EBBT would be the shorter treatment time11.

#### **5. Conclusion**

86 Brachytherapy

Macha et al9 365 5 Gy/3-4f 66% obstructive symptoms improvement

Kelly et al11 175 15 gy/1f 66% symptoms and 85% endoscopic

Petra et al12 67 5-7 Gy/1-2f 90% symptoms and 85% endoscopic

Celebioglu et al13 95 7-10 Gy/1-3f Significant reduction of symptoms,

Anacak et al15 28 7 Gy/3f 43% in cough, 80% in dyspnea and 95%

Table 5. Published results of HDR endobronchial brachytherapy as palliative treatment

to 6 fractions of 5 to 7 Gy (total 25 – 42 Gy) if this treatment is exclusively used 17.

EBBT has been used in curative treatment of lung cancer, both in the exclusive treatment of early tumors with EBRT as overprint (boost or reirradiation)2, 3. About the first indication, Marsiglia et al, reported a two year survival rate of 78% in 34 patients with small tumors without evidence of spread that were treated only with HDR-EBBT with a 30 Gy dose in 6 fractions3.Hennequin et al, in a series of 106 patients with localized tumors that were not candidates for surgery or EBRT, obtained a specific 3 and 5 years survival of 60% and 50% respectively2.The ABS recommended a healing (palliative) dose is 3 fractions of 5 to 7.5 Gy (total 15 – 22.5Gy) when the patient already received 60 Gy pretreatment with EBRT, and 5

Several authors have published interesting experiences regarding the use of EBBT in nonmalignant pathology. This treatment modality has been used successfully in patients with granulomatous proliferation after metal stent placement because of non-malignant airway

In patients who have not received EBRT it is feasible to use the combination of EBBT and EBRT in order to improve results. In a randomized study, the combination of those treatments proved to be more effective than single-EBRT in symptomatic improvement27. Mantz and colleagues, obtained a significant increase in local control when using a EBBT

Delclos et al14 81 15 Gy/1f 62% symptomatic improvement

**Results**

improvement

lesions improvement

lesion reduction

151 7 Gy/2-3f 99% of hemoptysis, 86% of dyspnea and

94% hemoptysis and 90% dyspnea reduction, 70% performance status

hemoptysis, dyspnea and cough

in hemoptysis Improvements

85% of cough improvements

**Dose and fraction**

Gy/1f GROUP B 7 Gy/2f GROUP C 5 Gy/3f

**Authors Nº**

Speicer and Spratling8

**2. Curative treatment**

**3. Non-oncologic pathology treatment**

stenosis, or pulmonary transplant patients4,5.

**of patients**

Muto et al10 320 GROUP A 10

The HDR-EBBT is a useful technique in the symptomatic treatment of ambulatory patients with central airway obstruction. The procedure is well tolerated and effective with low complications rate. Main indications are patients with advanced lung cancer, where the objective is only palliative. It must also be considered in situations of incipient tumors for patients with contraindications for surgery or EBRT, boosted after a first treatment with EBRT or in benign disease with endobronchial or endotracheal scar proliferation.

#### **6. References**

**Section 4**

**Novel Strategy and Applications**

## **Section 4**

**Novel Strategy and Applications**

88 Brachytherapy

[12] Petera J, Spasora I, Neumanova R y col. High-Dose-Rate Intraluminal brachytherapy in treatment of malignant airway obstruction. Neoplasma 2001;48:148-153 [13] Celebioglu B, Ural Gurkan O, Erdogan S y col. High dose rate endobronchyal

[14] Delclos ME, Komaki R, Morice RC y col. Endobronchyial brachytherapy with High-

[15] Anacak Y, Mogulkoc N, Ozkok S y col. High dose rate endobronchial brachitherapy in

[16] The Royal College of Radiologist. The Role and development of brachitherapy service in United Kingdom. London : the Royal College of Radiologyst, 2007 [17] Janssen JP, Noppen M and Rabe KF. Place of cryotherapy, brachytherapy and

[19] Van Limbergen E and Pötter R. Bonchus cancer in: Gerbaulet A, Potter R, Van

[20] Freitag L, Emst E, Thomas M y col. Sequential Photodinamic therapy and HDR

[21] Wang Jan T, Blackman G, George J. Survival benefits of lung cancer patients undergoing Laser an Brachytherapy . J Korean Med Sci 2002;17:341-7 [22] Escobar-Sacristán JA, Granada-Orive J, Gutierrrez T y col. Endobronchial

[23] Mehta M, Petereit D, Ghosy L y col. Sequential comparison of low-dose rate and

[24] Mallick I, Sharma S and Behera D. Endobronchyal brachytherapy for symptom

endoscopic improvement and quality of life. Lun Cancer 2007:55:313-318 [25] Bedwinek J, Petty A, Burton C y col. The use of higth dose rate endobronchyal

[27] Huber RM, Fischer R, Hautman H Y col. Does additional brachytherapy improve the

[28] Mantz C, Dosoretz E, Rubeistein H y col. Endobronchial brachytherapy and

carcinoma: A matched-pair analysis. Brachyterapy 2004;83;183.190

[18] Nag A. Brachytherapy for carcinoma of the lung. Oncology 2001;15(3): 371-81

Clin Oncol 2002.32(11);443-48

Lung cancer 2001.34:253-259

brachytherapy. ACCO, Belgium 2002

bronchogenic carcinoma. Thorax 2004;59:790-93

occlutions. Int J Radiat Oncol Biol Phys 192;23(1):133-39

component. Cancer Therapy 2004.2:469-74

tumors Int J radiat Oncol Biol Phys 1997;38:53-540

1996:201:279-282

2006;28:200-18

brachytherapy effectively palliates symptoms due to inoperable lung cancer. Jpn J

Dose-Rate Remote afterloading for recurrent endobroncyal leson. Radiology

combination with external beamradiotherapy for stage III non-smal cel lung cáncer.

photodynamic therapy in therapeutic bronchoscopy of lung cancer. Eur Respir J

Limbergen E, Mazeron JJ and Meertens H: GEC – ESTRO handboock of

brachytherapy for endobronchial tumor control in patients with limited

brachytherapy in the treatment of maingant lung tumors. Eur resp J 2004;24;348-52

hyperfractioned high-dose rate endobronchyal radiation for malignant airway

palliation in non-small cell lung cancer – Analysis of symptom response,

brachytherapy to palliate symptomatic endobronchyal recurrence of previously irradiated bronchogenic carcinoma. Int J Radiat Oncol Biol Phys 1992;22:23-30 [26] Lu JJ, Bains Y, Aaron B y col. High dose rate endobronchial brachytherapy for the

managent of non-small cell lung cancer with an endobronchial or peribronchial

effect of external irradiation? A prospective randomized study in central lung

optimization of local disease control in medically inoperble non-small cell lung

**6**

*Germany*

**Stereotactic Brachytherapy for Brain Tumors**

Brachytherapy for the treatment of brain tumors has a very long history and for selected indications still represents a safe, minimally invasive and effective local treatment option, offered by specialized centers. In the following chapter we review stereotactic brachytherapy (SBT) for brain tumors, including the history, physical aspects, surgical procedure, and indications, which are introduced and discussed in the context of the

In 1901, on Pierre Curie´s suggestion, Danlos inserted a radium isotope directly into a tumor. This is the first known use of interstitial irradiation, and was published later in 1905

Around the same time, in 1908 Horsley and Clarke introduced a 3D targeting stereotaxis apparatus to study a monkey's brain (Horsley & Clarke, 1908). The development of stereotactic techniques had begun. The first use of this apparatus in humans was performed in 1918 by Mussen (Picard et al., 1983). This technique allowed precise targeting of brain

The first implantation of a radioactive source into a structure of the CNS, more precisely into a tumor of the pituitary gland, was described by Hirsch in 1912 (Hirsch et al., 1912). Two years later, in 1914, Frazier reported for the first time the implantation of radioactive

Further development of this technology took place in the 1930s by introducing new

In the 1950's stereotactic guidance for the implantation of radioactive sources was used to precisely treat inoperable brain tumors. (Mundinger et al., 1956; Talairach et al., 1955)

In the 1970-80s implementing image-guided stereotactic surgery continuously improved the preciseness of placing the radioactive material into (malignant) brain tumors (McDermott et

techniques to improve accuracy in dosimetry for multiple implants (Patterson, 1934).

**1. Introduction**

available literature.

**2. History of brachytherapy for brain tumors**

structures for neurosurgical purposes.

material into glioma (Frazier, 1920).

al., 1998).

in *Journal de la Physiothérapie* (Bernstein & Gutin, 1981; Danlos, 1905).

Maximilian I. Ruge1, Stefan Grau2, Harald Treuer1 and Volker Sturm1

*1Department of Stereotaxy and Functional Neurosurgery, 2Department of Neurosurgery, University of Cologne,*

## **Stereotactic Brachytherapy for Brain Tumors**

Maximilian I. Ruge1, Stefan Grau2,

Harald Treuer1 and Volker Sturm1 *1Department of Stereotaxy and Functional Neurosurgery, 2Department of Neurosurgery, University of Cologne, Germany*

#### **1. Introduction**

Brachytherapy for the treatment of brain tumors has a very long history and for selected indications still represents a safe, minimally invasive and effective local treatment option, offered by specialized centers. In the following chapter we review stereotactic brachytherapy (SBT) for brain tumors, including the history, physical aspects, surgical procedure, and indications, which are introduced and discussed in the context of the available literature.

#### **2. History of brachytherapy for brain tumors**

In 1901, on Pierre Curie´s suggestion, Danlos inserted a radium isotope directly into a tumor. This is the first known use of interstitial irradiation, and was published later in 1905 in *Journal de la Physiothérapie* (Bernstein & Gutin, 1981; Danlos, 1905).

Around the same time, in 1908 Horsley and Clarke introduced a 3D targeting stereotaxis apparatus to study a monkey's brain (Horsley & Clarke, 1908). The development of stereotactic techniques had begun. The first use of this apparatus in humans was performed in 1918 by Mussen (Picard et al., 1983). This technique allowed precise targeting of brain structures for neurosurgical purposes.

The first implantation of a radioactive source into a structure of the CNS, more precisely into a tumor of the pituitary gland, was described by Hirsch in 1912 (Hirsch et al., 1912). Two years later, in 1914, Frazier reported for the first time the implantation of radioactive material into glioma (Frazier, 1920).

Further development of this technology took place in the 1930s by introducing new techniques to improve accuracy in dosimetry for multiple implants (Patterson, 1934).

In the 1950's stereotactic guidance for the implantation of radioactive sources was used to precisely treat inoperable brain tumors.

Stereotactic Brachytherapy for Brain Tumors 93

The radioactive seed(s) can be implanted in different ways. Some authors describe the placement of seeds without stereotactic guidance ("free hand") into the tumor or the cavity after microsurgical debulking of the tumor. This procedure has been described for metastasis and gliomas (Fernandez et al., 1995; Halligan et al., 1996; Patel et al., 2000; Schulder et al., 1997; Zamorano et al., 1992). This procedure, however, makes calculation of the dose distribution in the tissue very challenging, because seed location might shift over time when the resection cavity is changing its configuration. Furthermore, a later calculation

To date, the majority of groups place the seed(s) using stereotactic guidance. For this procedure a stereotactic computed tomography (CT) compatible frame is adjusted on the patient's head after inducing general or local anesthesia (Fig. 1a). We use both CT and magnetic resonance imaging (MRI) for the planning procedure: CT-imaging has the advantage of being less susceptible to distortions, while MR imaging provides better structural resolution of brain and tumor tissue. After CT imaging using a stereotactic localizer, CT scans are fused with MR images. Depending on the planning software, image fusion can be performed either automatically or by using anatomical landmarks (i.e. vessels) (Fig. 2a, CT scan; Fig 2b, MRI T1 weighed contrast). In some cases functional imaging such as functional MRI (fMRI) and/or positron emission tomography (PET) imaging can be

The next step is defining the target volume. Using MR (T2-, T1 contrast-, and in some cases FLAIR-weighed images), CT as well as - in specific cases - PET imaging, the visible margins of the tumor are outlined manually (Fig. 2c). The objective of radiation treatment planning for brain tumors is always to determine a seed configuration with as few seed catheters as possible (to minimize operative risk) and to achieve an optimal conformation of the therapeutic isodose with respect to the surface of the target volume (Treuer et al., 2005). Inverse treatment planning is used. The desired surface dose, implantation time, and trephination point(s) are selected manually and a seed configuration yielding optimal coverage of the tumor with the prescribed dose is calculated automatically by minimization

In the operation room, the stereotactic arc is adjusted on a phantom according to the

The 125Iodine seeds (Amersham Buchler GmbH & CoKG, Braunschweig, Germany) are introduced into celcon nylon or silicon catheters (Best Industries Inc., Springfield, VA, USA / Phoenix-Biomedical Corp., Ontario, Canada; Fig. 1b, c). After skin incision and placement of an 8 mm burr hole, the catheters are inserted into the tumor (Fig. 1d). In case histology is requested, a stereotactic biopsy can be taken and evaluated during the operation. To ensure correct placement of the seed(s) intraoperatively we perform X-ray imaging in two planes (anterior/posterior and lateral) with a stationary stereotactic X-ray source, and match these

of an appropriate objective function (Bauer-Kirpes et al., 1988) (Fig. 4).

images with images of the calculated trajectory (Fig. 3a, b).

calculated coordinates, and then mounted on the patient's stereotactic frame.

The value of accurate and common standards in dosimetry is obvious.

**4. Surgical procedure**

of the prescribed dose might also be challenging.

added (C-11-methionine, F-18-FET, F-18-FDG).

state that "changes in delivered dose from the introduction of the Model 6711 seed to the present have been less than 0.5% and can safely be ignored" (Willimson et al., 2005).

Since then, multiple studies have been published for the treatment of various intrinsic brain tumors, establishing (stereotactic) brachytherapy as a safe, minimally invasive, and effective neurosurgical technique for selected indications.

#### **3. Physical aspects**

Most frequently, Iodine-125-seeds (I-125) are used for stereotactic brachytherapy in brain tumors. Among a variety of possible radioactive sources used for brachytherapy, seeds containing I-125 are preferred for several reasons.

i. The energy of the emitted -rays (35.5 keV) and characteristic X-rays (27.2 – 31.7 keV) during the decay of I-125 is low (National Nuclear Data Center). This is advantageous, since such low energy photons are strongly absorbed in brain tissue (half-value layer: 2 cm) (Hubbell and Seltzer), yielding very high dose values inside the tumor, but additionally sparing surrounding healthy tissue. Thus the resulting dose gradient in brachytherapy with I-125-seeds is superior compared to stereotactic radiosurgery with external photon beams.

Furthermore, radiation emitted by I-125 is strongly absorbed in cortical bone (half-value layer: 3 mm) and can easily be shielded with lead (half-value layer: 0.02 mm). Thus radiation exposure of the patient's family and health care staff can be kept low.

The use of seeds with radio-opaque markers (such as Model 6711, Amersham Health) facilitates accurate intra-operative stereotactic localization of the seeds with X-rays or CT (Treuer et al., 2004). Thus the actual seed location during implantation can be determined and compared with the planned position. An accuracy of 1.5 mm in positioning of I-125-seeds was shown to be required in order to not inadequately compromise dose conformity (Treuer et al., 2005). With stereotactic guidance techniques such an accuracy requirement can be met.

Unlike other isotopes with low quantum energy, the dosimetry of I-125-seeds appears to be well understood. The main principles of the dosimetry of interstitial brachytherapy sources were defined in the report of the Task Group 43 of the American Association of Physicists in Medicine (AAPM) in 1995 (Nath et al., 1995). Recent recommendations of the AAPM, especially for the Amersham Model 6711 I-125-seed, state that "changes in delivered dose from the introduction of the Model 6711 seed to the present have been less than 0.5% and can safely be ignored" (Willimson et al., 2005). The value of accurate and common standards in dosimetry is obvious.

#### **4. Surgical procedure**

92 Brachytherapy

Since then, multiple studies have been published for the treatment of various intrinsic brain tumors, establishing (stereotactic) brachytherapy as a safe, minimally invasive, and effective

Most frequently, Iodine-125-seeds (I-125) are used for stereotactic brachytherapy in brain tumors. Among a variety of possible radioactive sources used for brachytherapy, seeds

i. The energy of the emitted -rays (35.5 keV) and characteristic X-rays (27.2 – 31.7 keV) during the decay of I-125 is low (National Nuclear Data Center). This is advantageous, since such low energy photons are strongly absorbed in brain tissue (half-value layer: 2 cm) (Hubbell and Seltzer), yielding very high dose values inside the tumor, but additionally sparing surrounding healthy tissue. Thus the resulting dose gradient in brachytherapy with I-125-seeds is superior compared to stereotactic radiosurgery with

Furthermore, radiation emitted by I-125 is strongly absorbed in cortical bone (half-value layer: 3 mm) and can easily be shielded with lead (half-value layer: 0.02 mm). Thus

The use of seeds with radio-opaque markers (such as Model 6711, Amersham Health) facilitates accurate intra-operative stereotactic localization of the seeds with X-rays or CT (Treuer et al., 2004). Thus the actual seed location during implantation can be determined and compared with the planned position. An accuracy of 1.5 mm in positioning of I-125-seeds was shown to be required in order to not inadequately compromise dose conformity (Treuer et al., 2005). With stereotactic guidance techniques

Unlike other isotopes with low quantum energy, the dosimetry of I-125-seeds appears to be well understood. The main principles of the dosimetry of interstitial brachytherapy sources were defined in the report of the Task Group 43 of the American Association of Physicists in Medicine (AAPM) in 1995 (Nath et al., 1995). Recent recommendations of the AAPM, especially for the Amersham Model 6711 I-125-seed,

radiation exposure of the patient's family and health care staff can be kept low. ii. The half-life of I-125 is rather long, 59.4 days (National Nuclear Data Center); hence the dose rate decreases by only 1.16% per day during irradiation. This allows extension of irradiation times to several weeks or longer, with only slowly decreasing dose rates. For example, a total dose of 60 Gy accumulated in 42 days equals a dose rate of as high as 1.8 Gy/day at the beginning and still 1.1 Gy/day at the end of treatment. Long-term

irradiation regiments appear favorable, especially for slow-growing tumors. iii. I-125-seeds of different type and source strength are readily available on the market (Heintz et al., 2001). The option to select seeds with activities ranging from 0.5 mCi – 10 mCi is a prerequisite for creating conformal treatment plans for brain tumors with a low number of seed-catheters. In fact, with I-125-seeds highly conformal treatment plans with conformity indices ranging from 48% – 79% (mean 70%) can be created for brain tumors by applying as few as 1 – 3 catheters (mean 1.8) and 1 – 6 seeds per catheter (mean 2.4) (Treuer et al., 2005). Implanting a low number of catheters in the brain minimizes the operative risks of bleeding and infections, and reduces operation time,

and thus problems due to brain shift (Hunsche et al., 2009).

such an accuracy requirement can be met.

neurosurgical technique for selected indications.

containing I-125 are preferred for several reasons.

**3. Physical aspects**

external photon beams.

The radioactive seed(s) can be implanted in different ways. Some authors describe the placement of seeds without stereotactic guidance ("free hand") into the tumor or the cavity after microsurgical debulking of the tumor. This procedure has been described for metastasis and gliomas (Fernandez et al., 1995; Halligan et al., 1996; Patel et al., 2000; Schulder et al., 1997; Zamorano et al., 1992). This procedure, however, makes calculation of the dose distribution in the tissue very challenging, because seed location might shift over time when the resection cavity is changing its configuration. Furthermore, a later calculation of the prescribed dose might also be challenging.

To date, the majority of groups place the seed(s) using stereotactic guidance. For this procedure a stereotactic computed tomography (CT) compatible frame is adjusted on the patient's head after inducing general or local anesthesia (Fig. 1a). We use both CT and magnetic resonance imaging (MRI) for the planning procedure: CT-imaging has the advantage of being less susceptible to distortions, while MR imaging provides better structural resolution of brain and tumor tissue. After CT imaging using a stereotactic localizer, CT scans are fused with MR images. Depending on the planning software, image fusion can be performed either automatically or by using anatomical landmarks (i.e. vessels) (Fig. 2a, CT scan; Fig 2b, MRI T1 weighed contrast). In some cases functional imaging such as functional MRI (fMRI) and/or positron emission tomography (PET) imaging can be added (C-11-methionine, F-18-FET, F-18-FDG).

The next step is defining the target volume. Using MR (T2-, T1 contrast-, and in some cases FLAIR-weighed images), CT as well as - in specific cases - PET imaging, the visible margins of the tumor are outlined manually (Fig. 2c). The objective of radiation treatment planning for brain tumors is always to determine a seed configuration with as few seed catheters as possible (to minimize operative risk) and to achieve an optimal conformation of the therapeutic isodose with respect to the surface of the target volume (Treuer et al., 2005). Inverse treatment planning is used. The desired surface dose, implantation time, and trephination point(s) are selected manually and a seed configuration yielding optimal coverage of the tumor with the prescribed dose is calculated automatically by minimization of an appropriate objective function (Bauer-Kirpes et al., 1988) (Fig. 4).

In the operation room, the stereotactic arc is adjusted on a phantom according to the calculated coordinates, and then mounted on the patient's stereotactic frame.

The 125Iodine seeds (Amersham Buchler GmbH & CoKG, Braunschweig, Germany) are introduced into celcon nylon or silicon catheters (Best Industries Inc., Springfield, VA, USA / Phoenix-Biomedical Corp., Ontario, Canada; Fig. 1b, c). After skin incision and placement of an 8 mm burr hole, the catheters are inserted into the tumor (Fig. 1d). In case histology is requested, a stereotactic biopsy can be taken and evaluated during the operation. To ensure correct placement of the seed(s) intraoperatively we perform X-ray imaging in two planes (anterior/posterior and lateral) with a stationary stereotactic X-ray source, and match these images with images of the calculated trajectory (Fig. 3a, b).

Stereotactic Brachytherapy for Brain Tumors 95

c

Fig. 2. Image fusion of CT and MRI scans. a) CT image; b) MRI image. c) The blue dotted

Fig. 3. The stereotactic treatment plan. a) Positioning of the catheters and seeds, which is then compared with b) the two plane X-ray images performed after final placement of the

line represents the manually outlined tumor margin.

a b

seeds-catheters by over-laying.

a

b

Fig. 1. Steps involved in stereotactic brachytherapy. *a) Stereotactic frame with localizer. b) Iodine-125 seed compared to a coffee bean. c) The first catheter is placed stereotactically in the target volume (above). The second catheter is filled with the calculated seed(s) (middle) which are fixed by insertion of a thin tube (below) and then placed in the first catheter. d) Operative setting with the stereotactic frame, the stereotactic arc and the inserted seed catheter.*

b

a

d

c

Fig. 1. Steps involved in stereotactic brachytherapy. *a) Stereotactic frame with localizer. b) Iodine-125 seed compared to a coffee bean. c) The first catheter is placed stereotactically in the target volume (above). The second catheter is filled with the calculated seed(s) (middle) which are fixed by insertion of a thin tube (below) and then placed in the first catheter. d) Operative setting with the*

*stereotactic frame, the stereotactic arc and the inserted seed catheter.*

Fig. 2. Image fusion of CT and MRI scans. a) CT image; b) MRI image. c) The blue dotted line represents the manually outlined tumor margin.

Fig. 3. The stereotactic treatment plan. a) Positioning of the catheters and seeds, which is then compared with b) the two plane X-ray images performed after final placement of the seeds-catheters by over-laying.

Stereotactic Brachytherapy for Brain Tumors 97

Compared to intraoperative CT or MRI scanning used by some groups to monitor laser thermal therapy or placement of DBS electrodes, this technique does not require movement of the patient or a time-consuming imaging session. Furthermore, it is comparatively fast, repeatable, and even allows monitoring of the (re-)positioning of the catheters containing the I-125 seeds with high precision and with a comparatively low radiation burden for the patient (Treuer et al., 2005, Ruge et al, 2011a;b;c;d). For stabilization, the catheters are fixed within the burr hole using bone cement. In addition, the catheter tip, protruding out of the cement by approximately 3-5 mm, is fixed with a vessel clip to further avoid displacement. In the rare cases of intraoperatively detected incorrect placement of the implanted seeds, we primarily revise the catheter position. If this revision is not satisfactory, the isodose plan is

Finally, the emitted radiation is measured at 1 m and 2 m distances from the patent's head. In cases where the dose rate exceeds 2 µSv/h at 1 m distance, the patient has to temporarily

The duration of the surgical procedure is usually between 40 minutes and 1.5 hours, depending on the number of catheters used. The patient's hospital stay varies between 3–5

Seed catheters if implanted temporarily are removed under local anesthesia by removing the vessel clip and extracting the catheter, leaving the cement within the burr hole. This procedure requires a hospital stay of one day in most cases. At this time every patient receives a follow-up MRI using the same imaging protocol as in the SBT planning to ensure

SBT was initially considered to be indicated for patients with a circumscribed tumor with a maximum diameter of 5 cm on CT or MRI scans. Based on available risk analysis (Kreth et al., 1997), the treatment is now widely restricted to well circumscribed tumors with a diameter not larger than 4 cm. Kreth et al. demonstrated that beyond a cut-off of approximately 3.5 cm tumor diameter (or a tumor volume of 22.4 ml) radiogenic complications increase exponentially (Kreth et al., 1997). Furthermore, the volume of the high dose irradiation zone

Patients with non-circumscribed (diffuse) tumors, or with tumors of the corpus callosum, hypothalamus, fornices, or optical system (optical nerve, chiasm) are not considered suitable

Among the variety of intracranial neoplasms, data from larger series exist for intracranial gliomas and metastatic brain tumors. Therefore, indication for brachytherapy should focus on these entities, while application of brachytherapy for other, rare indications, which are

Malignant gliomas are non-curable intrinsic tumors of the central nervous system with a rate of almost 100% recurrence and intracranial spread. Despite improvements in different therapeutic modalities, glioblastoma still bear an overall survival rate of 12-15 months (Oertel

(200 Gy isodose) also correlates directly with radiation induced tissue damage.

recalculated and the irradiation time adjusted accordingly.

**5. Indications for Stereotactic Brachytherapy (SBT)**

only mentioned briefly, should be carefully considered.

**5.1 SBT for high-grade gliomas (WHO III & IV)**

wear a lead cap (Voges et al., 1999).

days.

comparability.

for this treatment.

Fig. 4. An irradiation plan of an anaplastic astrocytoma WHO III in the left central sulcus area *(see also case report in Fig. 5).  The dark blue dotted line represents the manually outlined tumor surface, the green line represents the 50 Gy isodose, the red line the 65 Gy isodose and yellow the 200 Gy isodose line. b) The straight red line in a) shows the simulated catheter containing the I-125 seeds.*

a b

c d

e f

Fig. 4. An irradiation plan of an anaplastic astrocytoma WHO III in the left central sulcus area *(see also case report in Fig. 5).  The dark blue dotted line represents the manually outlined tumor surface, the green line represents the 50 Gy isodose, the red line the 65 Gy isodose and yellow the 200 Gy isodose line. b) The straight red line in a) shows the simulated catheter containing the I-125 seeds.*

Compared to intraoperative CT or MRI scanning used by some groups to monitor laser thermal therapy or placement of DBS electrodes, this technique does not require movement of the patient or a time-consuming imaging session. Furthermore, it is comparatively fast, repeatable, and even allows monitoring of the (re-)positioning of the catheters containing the I-125 seeds with high precision and with a comparatively low radiation burden for the patient (Treuer et al., 2005, Ruge et al, 2011a;b;c;d). For stabilization, the catheters are fixed within the burr hole using bone cement. In addition, the catheter tip, protruding out of the cement by approximately 3-5 mm, is fixed with a vessel clip to further avoid displacement.

In the rare cases of intraoperatively detected incorrect placement of the implanted seeds, we primarily revise the catheter position. If this revision is not satisfactory, the isodose plan is recalculated and the irradiation time adjusted accordingly.

Finally, the emitted radiation is measured at 1 m and 2 m distances from the patent's head. In cases where the dose rate exceeds 2 µSv/h at 1 m distance, the patient has to temporarily wear a lead cap (Voges et al., 1999).

The duration of the surgical procedure is usually between 40 minutes and 1.5 hours, depending on the number of catheters used. The patient's hospital stay varies between 3–5 days.

Seed catheters if implanted temporarily are removed under local anesthesia by removing the vessel clip and extracting the catheter, leaving the cement within the burr hole. This procedure requires a hospital stay of one day in most cases. At this time every patient receives a follow-up MRI using the same imaging protocol as in the SBT planning to ensure comparability.

#### **5. Indications for Stereotactic Brachytherapy (SBT)**

SBT was initially considered to be indicated for patients with a circumscribed tumor with a maximum diameter of 5 cm on CT or MRI scans. Based on available risk analysis (Kreth et al., 1997), the treatment is now widely restricted to well circumscribed tumors with a diameter not larger than 4 cm. Kreth et al. demonstrated that beyond a cut-off of approximately 3.5 cm tumor diameter (or a tumor volume of 22.4 ml) radiogenic complications increase exponentially (Kreth et al., 1997). Furthermore, the volume of the high dose irradiation zone (200 Gy isodose) also correlates directly with radiation induced tissue damage.

Patients with non-circumscribed (diffuse) tumors, or with tumors of the corpus callosum, hypothalamus, fornices, or optical system (optical nerve, chiasm) are not considered suitable for this treatment.

Among the variety of intracranial neoplasms, data from larger series exist for intracranial gliomas and metastatic brain tumors. Therefore, indication for brachytherapy should focus on these entities, while application of brachytherapy for other, rare indications, which are only mentioned briefly, should be carefully considered.

#### **5.1 SBT for high-grade gliomas (WHO III & IV)**

Malignant gliomas are non-curable intrinsic tumors of the central nervous system with a rate of almost 100% recurrence and intracranial spread. Despite improvements in different therapeutic modalities, glioblastoma still bear an overall survival rate of 12-15 months (Oertel

Stereotactic Brachytherapy for Brain Tumors 99

**a**

**b**

**c**

**d**

**MRI 9/2008**

**MRI 9/2011**

Fig. 5. MRI of a patient with anaplastic astrocytoma WHO III. *MRI scans of an 41 year old patient diagnosed by stereotactic biopsy with an anaplastic astrocytoma WHO III in September 2008; a) T1- with contrast, b) T2-weighed images. According to our protocol he underwent stereotactic brachytherapy (I-125, 50 Gy cumulative tumor surface dose, permanent implantation) followed by 25 Gy EBRT boost. c, d) Follow-up MRI shows partial response of the tumor two years later. The*

*patient's initial paresis of the right hand resolved completely.*

et al., 2005; Salcman, 2001). On MRI/CT scans they usually present as a heterogeneously contrast enhancing lesion with central necrosis. With respect to treatment, radiotherapy has turned out to have the biggest impact on tumor control, time to progression, and overall survival in patients with malignant gliomas (Walker et al., 1978; 1980). To date, a multimodal approach has shown prolonged overall survival and improved quality of life (Brem et al., 1995; Stupp et al., 2005).

The extent of surgical removal of the contrast-enhancing mass has been correlated with improved overall survival (Stummer et al., 2006). However, surgical treatment is frequently limited due to the location and extension of the tumor into eloquent brain areas.

For deep-seated, non-resectable tumors, brachytherapy may theoretically be an interesting treatment alternative, affording low surgical risk and limited, local application of an effective radiation dose (Fig. 5). However, the fact that these tumors show highly invasive behavior limits this theoretically attractive approach.

Several larger studies were published predominantly in the 1980s and 1990s on brachytherapy for malignant gliomas as a primary treatment modality, or in combination with surgical removal, external beam radiation therapy (EBRT) and chemotherapy (Fermandez et al., 1995; Gutin et al., 1991; Kreth et al., 1994; Malkin et al., 1994; Scharfen et al., 1992; Sneed et al., 1998; Videtic et al., 2001; Wen et al., 1994; Zamorano et al., 1992). After thorough analysis, these studies have failed to show significant benefits in terms of time to progression (TTP) or overall survival (OS) in these patients, including patients in two randomized controlled trials (Laperriere et al., 1998; Selker et al., 2002). Furthermore, a relevant number of radiation-induced necroses requiring subsequent surgical resection were described, which is attributed to the predominantly high activity/high dose rate implantation regimens chosen due to the high proliferation rate of these tumors.

Notably, all these data were retrieved in an era prior to temozolomide, and were frequently based on CT rather than MRI findings, a fact that may further compound the derived conclusions. In the light of more recent data demonstrating the efficacy of surgery and radio-chemotherapy, brachytherapy for newly diagnosed malignant glioma does not represent a standard therapy and should not be favored over standard therapy. There is also no recent evidence supporting a combined approach with brachytherapy after surgical resection and in combination with EBRT.

Novel approaches combining brachytherapy with EBRT and chemotherapy for deep-seated, non-respectable tumors as a first line treatment are under clinical investigation, but data are not available yet.

As mentioned above, malignant gliomas show extremely high recurrence rates despite intensive and combined therapy. Therefore, the first studies on brachytherapy for intracranial tumors were performed on recurrent gliomas. In this particular setting, a series of permanent or temporary implants with different dose rates were reported to have variable outcomes in terms of overall survival and progression free survival (Gutin et al., 1984; 1987; Halligan et al., 1996; Julow et al., 2007; Kitchen et al., 1994; Larson et al., 2004; Patel et al., 2000; Ryken et al., 1994; Tselis et al., 2007). The published studies showed no evidence for a significant benefit from brachytherapy in recurrent glioblastoma, although probably a subset of patients may benefit from this treatment. Nevertheless, the method still may be applied as a salvage option in selected patients.

et al., 2005; Salcman, 2001). On MRI/CT scans they usually present as a heterogeneously contrast enhancing lesion with central necrosis. With respect to treatment, radiotherapy has turned out to have the biggest impact on tumor control, time to progression, and overall survival in patients with malignant gliomas (Walker et al., 1978; 1980). To date, a multimodal approach has shown prolonged overall survival and improved quality of life (Brem et al.,

The extent of surgical removal of the contrast-enhancing mass has been correlated with improved overall survival (Stummer et al., 2006). However, surgical treatment is frequently

For deep-seated, non-resectable tumors, brachytherapy may theoretically be an interesting treatment alternative, affording low surgical risk and limited, local application of an effective radiation dose (Fig. 5). However, the fact that these tumors show highly invasive

Several larger studies were published predominantly in the 1980s and 1990s on brachytherapy for malignant gliomas as a primary treatment modality, or in combination with surgical removal, external beam radiation therapy (EBRT) and chemotherapy (Fermandez et al., 1995; Gutin et al., 1991; Kreth et al., 1994; Malkin et al., 1994; Scharfen et al., 1992; Sneed et al., 1998; Videtic et al., 2001; Wen et al., 1994; Zamorano et al., 1992). After thorough analysis, these studies have failed to show significant benefits in terms of time to progression (TTP) or overall survival (OS) in these patients, including patients in two randomized controlled trials (Laperriere et al., 1998; Selker et al., 2002). Furthermore, a relevant number of radiation-induced necroses requiring subsequent surgical resection were described, which is attributed to the predominantly high activity/high dose rate