**2.1 Conventional radiotherapy**

Introducing high-energy radiotherapy machines it become possible to deliver tumoricidal doses to target volume while minimizing damage to the skin and adjacent organs. Historically, various techniques have been used, ranging from parallel anteroposterior- /posteroanterior (AP/PA) portals to lateral portals (box technique) or rotational fields to irradiate or supplement the dose to the prostate. (Chao et al, 2002) Due to the difficulty of localizing the prostate gland, a large volume was treated to ensure proper coverage. More of the surrounding tissues were included in the treated volume so the safely applicable dose was limited to 60-65Gy. (Choe & Liauw, 2010)

The treatment fields for prostate cancer were simulated and designed on plane films and using bony markers with the patient in the supine position. Rectum and bladder were marked by intraluminal injection of iodinated contrast. Small intestine was marked with barium contrast ingested per os one hour prior to simulation.

If the external-beam radiotherapy was applied to the prostate only (local technique), the field size was approximately 8x10 cm for T1 and T2 tumors, 10x12 cm or 12x14 cm for T3 and T4 prostate cancer. Patients younger than 71 years of age with clinical T1c, T2a, and Gleason score more than 7 and PSA 20ng/ml or more, as well as patients with T2b, c T3 and T4 were treated to the whole pelvis with the field size of 15x15 cm, or 15x18 cm to cover the common iliac nodes. The inferior margin of the field usually was 1.5 cm distal to the junction of the prostatic and membranous urethra that is at or caudal to the bottom of the ischial tuberosities. The lateral margins were approximately 1 to 2 cm from the lateral bony pelvis.

Fig. 1. Simulation AP radiograph for field verification (a) size 12x12 cm and (b) 14x14 cm Low field border is on the lower border of ishiadic bone and the field centre on the symphisis. Barium contrast in bowels (With thanks to the Institute for oncology and radiology of Serbia, Belgrade)

In the last 30 years it has undergone a long, improving path from conventional, twodimensional radiotherapy to intensity-modulated and image-guided radiotherapy and onwards. In low-risk prostate cancer its efficacy appears to be comparable to that of radical prostatectomy but with different toxicities (Choe & Liauw, 2010). For patients not suitable for surgery, external-beam radiotherapy will be the treatment of choice in most cases, alone

Introducing high-energy radiotherapy machines it become possible to deliver tumoricidal doses to target volume while minimizing damage to the skin and adjacent organs. Historically, various techniques have been used, ranging from parallel anteroposterior- /posteroanterior (AP/PA) portals to lateral portals (box technique) or rotational fields to irradiate or supplement the dose to the prostate. (Chao et al, 2002) Due to the difficulty of localizing the prostate gland, a large volume was treated to ensure proper coverage. More of the surrounding tissues were included in the treated volume so the safely applicable dose

The treatment fields for prostate cancer were simulated and designed on plane films and using bony markers with the patient in the supine position. Rectum and bladder were marked by intraluminal injection of iodinated contrast. Small intestine was marked with

If the external-beam radiotherapy was applied to the prostate only (local technique), the field size was approximately 8x10 cm for T1 and T2 tumors, 10x12 cm or 12x14 cm for T3 and T4 prostate cancer. Patients younger than 71 years of age with clinical T1c, T2a, and Gleason score more than 7 and PSA 20ng/ml or more, as well as patients with T2b, c T3 and T4 were treated to the whole pelvis with the field size of 15x15 cm, or 15x18 cm to cover the common iliac nodes. The inferior margin of the field usually was 1.5 cm distal to the junction of the prostatic and membranous urethra that is at or caudal to the bottom of the ischial tuberosities. The

(a) (b)

Fig. 1. Simulation AP radiograph for field verification (a) size 12x12 cm and (b) 14x14 cm Low field border is on the lower border of ishiadic bone and the field centre on the symphisis. Barium contrast in bowels (With thanks to the Institute for oncology and

or combined with androgen-deprivation therapy.

was limited to 60-65Gy. (Choe & Liauw, 2010)

barium contrast ingested per os one hour prior to simulation.

lateral margins were approximately 1 to 2 cm from the lateral bony pelvis.

**2.1 Conventional radiotherapy** 

radiology of Serbia, Belgrade)

The initial lateral fields included a volume similar to that treated with AP/PA portals. The anterior margin was 1.5 cm posterior to the projection of the anterior cortex of the pubic symphisis. Posteriorly, the fields included the pelvic and presacral lymph nodes above the S3 segment, which allowed some sparing of posterior rectal wall distal to this level.

Large treated volume was obtained since the average variation of prostate position relative to bony markers was approximately 8 mm in the superior and posterior positions, 7 mm in the inferior, 5 mm in the lateral and 4 mm in anterior position. The seminal vesicles are located high in the pelvis, and posterior to the bladder, which was very critical when reducing treated volume in T3 patients.

When indicated, the periaortic lymph nodes could be treated through extended AP/PA portals or separate periaortic fields placed above the pelvic fields. The superior margin of the periaortic field was at the Th12-L1 vertebral interspace with the width usually above 10 cm (determined by lymphangiogram or CT scan). (Chao et al., 2002, Dobbs et al., 1999)

Conventional external-beam radiotherapy required daily radiation delivery to target volume using high-energy beams (more than 10MV). In most institutions a standard fractionation was used with 1.8 to 2Gy per day. In radical approach, initially a dose of 45- 50Gy was applied to the whole pelvis or to the prostate through two parallel opposed fields (AP/PA). Than addition of a boost dose was delivered, up to a total dose of 65-66Gy through lateral opposed fields, two anterior or two posterior oblique fields. (Chao et al., 2002, Dobbs et al., 1999)

#### **2.2 Two-dimensional radiotherapy (2D-RT)**

Once a decision is being made to treat prostate cancer with external-beam radiotherapy, the radiotherapy plan is defined either to limit treatment to the gland or to extend treatment field to include the periprostatic tissues, seminal vesicles and pelvic lymph nodes. (Hayden et al. 2010) CT or MRI of the abdomen and pelvis is used to assess the involvement of surrounding structures. MRI is particularly useful for distinguishing capsular invasion, seminal vesicle involvement and periapical extension. CT scanning for treatment planning is performed to every patient, which means that two-dimensional (2D) radiotherapy is a step forward comparing to conventional radiotherapy.

The patient is immobilized in supine position with skin tattoos over the pubic symphisis and laterally over the iliac crests to prevent lateral rotation. CT scans of pelvis are obtained with slice thickness of 4-5 mm. No oral, rectal or intravenous contrast is used. The CT section at the centre of the volume is used as the main planning slice to outline patient contour, target volume, rectum, and bladder. The margins of the target volume are determined by the tumor extent. The gross tumor volume contains entire prostate gland, but if there is a risk of seminal vesicles involvement, they must be included in target volume too. The gross tumor volume is outlined on the central slice only. To allow position variation, an additional margin is added to gross tumor volume (1-1.5 cm in all directions) defining planning target volume (PTV). For two-dimensional planning, PTV is outlined on multiple sections to ensure that the entire tumor is encompassed. The rectal outline must be transposed on to the central section so that the dose can be adequately calculated. Shaping the target volume by shielding blocks or multileaf collimators reduces the dose to normal tissues.

Treatment technique depends on the target volume size and shape. Three-field technique using an anterior and two posterior oblique or opposed lateral fields give a high dose to the

cases were seminal vesicle involvement is proven, whole of them should be included in CTV. Any extracapsular extension is also delineated under the CTV, and even a margin of 2-5 mm (excluding rectum) should be considered in high–risk and T3 disease. (Hayden et al., 2010, Koh et al., 2003, Boehmer et al., 2006) According to RTOG guidelines in 2009, pelvic lymph node irradiation may be considered in high-risk patients judged by the treating clinician. The risk of lymph node involvement approaches the risk of distant metastases so the benefit of

PTV is a margin added to CTV to reduce the impact of set-up error and organ motion on CTV displacement. PTV also covers inter-observer variability in both delineating of mentioned structures and verification process. According to RTOG recommendation, a PTV is determined by institutional set-up and verification protocol, and measurement of institutional random and systemic errors of prostate position. (Lawton et al., 2009) In many institutions the acceptable CTV-PTV margin ranges from 5 do 10 mm. (Hayden et

(a) (b)

(c) (d)

Fig. 2. Delineation of target volume (prostate-pink and seminal vesicles-purple) and organs

at risk (bladder-green, rectum-red and femoral heads-light green and dark green) delineation. PTV margin-magenta (a, b, c). Sagital reconstruction (d). (With thanks to the

Institute for oncology and radiology of Serbia, Belgrade)

lymph node irradiation remains controversial. (Lawton et al., 2009)

al., 2010) (Figure 2.)

prostate but spare the posterior rectal wall. Four-field (box) technique may result in better dose distribution when seminal vesicles are included in target volume, but increases the dose posteriorly.

The patient is than treated daily, 1.8 to 2Gy per fraction, on linear accelerator. The correct position is assured with skin tattoos. The field centre is marked with a tattoo also. All fields are treated isocentrically with shielding as instructed. The recommended dose is 64Gy in 32 fractions given in 6.5 to 7 weeks. (Dobbs et al., 1999)

### **2.3 Three-dimensional conformal radiotherapy (3D-CRT)**

Introducing CT-based radiotherapy simulations by the mid 1980s and multileaf collimator in new aged linear accelerators, it became possible to arrange treatment fields to individually match prostate target volume minimizing high dose exposure to adjacent normal tissues. This led to dose escalation without inducing more toxicity and implementing three-dimensional conformal radiotherapy in clinical practice as a gold standard in prostate cancer radiotherapy treatment. Practically, the aim is to minimize treatment toxicity for patients with more favorable disease, and to maximize locoregional tumor control for those with less favorable disease. (Hayden et al., 2010, Dearnaley, 2001, Gazdda et al., 1996/97)

For 3D-CRT treatment planning a multi-slice CT scan and 3D planning system is used. In order to minimize random and systemic setup error, prior to CT scan, patient should be positioned and immobilized in a fashion that position obtained can be maintained and reproduced. This is secured by the use of alpha cradles, shells or by positioning the patient in supine position with leg restraints. In all this cases a midline and lateral laser lights are used for set up. These markers are tattooed on the skin over the pubic symphisis and laterally over the iliac crests. This is very important for daily positioning of the patient and prevention of lateral rotation. The position is later verified by portal image. (Dobbs et al., 1999, Hayden et al., 2010, Malone et al., 2000)

CT scan of pelvis is performed in a treatment position. Patient should empty the rectum and the bladder should be comfortably full both on the simulation and on the radiation. This standard should be followed because the variation in bladder and rectum distension results in significant prostate displacement. A great controversy still remains regarding prostate apex. MRI of pelvis and CT/MRI fusion is recommended to reduce interobserver variability in contouring, improving target delineation accuracy, particularly the prostate apex. This fusion is also recommended were significant CT artifact is present i.e. from hip prosthesis.

Once the CT and/or MRI scans are obtained on each slice a target volume and organs at risk are delineated. Organs at risk are adjacent structures endangered by high radiation dose delivered to treated volume. These organs include bladder, rectum, femoral heads and small bowel when it is in the treatment field. (Fiorino et al., 2009)

In 3D-CRT of prostate cancer target volume consists of clinical target volume (CTV) and planning target volume (PTV). CTV includes prostate only, or prostate with seminal vesicles and lymph nodes depending on risk category of the disease. In low-risk prostate cancer, the risk of seminal vesicles involvement is less than 5%, so the CTV should be restricted to prostate only. But, for intermediate risk patients the risk of seminal vesicle involvement is higher (over 15%) hence the proximal third of the seminal vesicles (1 cm) should be included in CTV. For high-risk patients proximal 2 cm of seminal vesicles should be in encompassed with CTV. In

prostate but spare the posterior rectal wall. Four-field (box) technique may result in better dose distribution when seminal vesicles are included in target volume, but increases the

The patient is than treated daily, 1.8 to 2Gy per fraction, on linear accelerator. The correct position is assured with skin tattoos. The field centre is marked with a tattoo also. All fields are treated isocentrically with shielding as instructed. The recommended dose is 64Gy in 32

Introducing CT-based radiotherapy simulations by the mid 1980s and multileaf collimator in new aged linear accelerators, it became possible to arrange treatment fields to individually match prostate target volume minimizing high dose exposure to adjacent normal tissues. This led to dose escalation without inducing more toxicity and implementing three-dimensional conformal radiotherapy in clinical practice as a gold standard in prostate cancer radiotherapy treatment. Practically, the aim is to minimize treatment toxicity for patients with more favorable disease, and to maximize locoregional tumor control for those with less favorable disease. (Hayden et al., 2010, Dearnaley, 2001,

For 3D-CRT treatment planning a multi-slice CT scan and 3D planning system is used. In order to minimize random and systemic setup error, prior to CT scan, patient should be positioned and immobilized in a fashion that position obtained can be maintained and reproduced. This is secured by the use of alpha cradles, shells or by positioning the patient in supine position with leg restraints. In all this cases a midline and lateral laser lights are used for set up. These markers are tattooed on the skin over the pubic symphisis and laterally over the iliac crests. This is very important for daily positioning of the patient and prevention of lateral rotation. The position is later verified by portal image. (Dobbs et al.,

CT scan of pelvis is performed in a treatment position. Patient should empty the rectum and the bladder should be comfortably full both on the simulation and on the radiation. This standard should be followed because the variation in bladder and rectum distension results in significant prostate displacement. A great controversy still remains regarding prostate apex. MRI of pelvis and CT/MRI fusion is recommended to reduce interobserver variability in contouring, improving target delineation accuracy, particularly the prostate apex. This fusion is also recommended were significant CT artifact is present i.e.

Once the CT and/or MRI scans are obtained on each slice a target volume and organs at risk are delineated. Organs at risk are adjacent structures endangered by high radiation dose delivered to treated volume. These organs include bladder, rectum, femoral heads and small

In 3D-CRT of prostate cancer target volume consists of clinical target volume (CTV) and planning target volume (PTV). CTV includes prostate only, or prostate with seminal vesicles and lymph nodes depending on risk category of the disease. In low-risk prostate cancer, the risk of seminal vesicles involvement is less than 5%, so the CTV should be restricted to prostate only. But, for intermediate risk patients the risk of seminal vesicle involvement is higher (over 15%) hence the proximal third of the seminal vesicles (1 cm) should be included in CTV. For high-risk patients proximal 2 cm of seminal vesicles should be in encompassed with CTV. In

dose posteriorly.

Gazdda et al., 1996/97)

from hip prosthesis.

fractions given in 6.5 to 7 weeks. (Dobbs et al., 1999)

1999, Hayden et al., 2010, Malone et al., 2000)

bowel when it is in the treatment field. (Fiorino et al., 2009)

**2.3 Three-dimensional conformal radiotherapy (3D-CRT)** 

cases were seminal vesicle involvement is proven, whole of them should be included in CTV. Any extracapsular extension is also delineated under the CTV, and even a margin of 2-5 mm (excluding rectum) should be considered in high–risk and T3 disease. (Hayden et al., 2010, Koh et al., 2003, Boehmer et al., 2006) According to RTOG guidelines in 2009, pelvic lymph node irradiation may be considered in high-risk patients judged by the treating clinician. The risk of lymph node involvement approaches the risk of distant metastases so the benefit of lymph node irradiation remains controversial. (Lawton et al., 2009)

PTV is a margin added to CTV to reduce the impact of set-up error and organ motion on CTV displacement. PTV also covers inter-observer variability in both delineating of mentioned structures and verification process. According to RTOG recommendation, a PTV is determined by institutional set-up and verification protocol, and measurement of institutional random and systemic errors of prostate position. (Lawton et al., 2009) In many institutions the acceptable CTV-PTV margin ranges from 5 do 10 mm. (Hayden et al., 2010) (Figure 2.)

Fig. 2. Delineation of target volume (prostate-pink and seminal vesicles-purple) and organs at risk (bladder-green, rectum-red and femoral heads-light green and dark green) delineation. PTV margin-magenta (a, b, c). Sagital reconstruction (d). (With thanks to the Institute for oncology and radiology of Serbia, Belgrade)

(a) (b)

Fig. 4. Digitaly reconstructed radiographs (DRR) for AP (a) and right lateral (b) field (With

Fig. 5. Dose-volume-histogram (DVH) showing the doses delivered to each delineated structure (With thanks to the Institute for oncology and radiology of Serbia, Belgrade)

thanks to the Institute for oncology and radiology of Serbia, Belgrade)

When the delineation process is completed, the medical physicists arrange beam angles and adjust them to maximize target coverage and minimize high-dose exposure to normal organs. (Choe & Liauw, 2010) (Figure 3.)

Fig. 3. Field arrangement for four-field (box) treatment (With thanks to the Institute for oncology and radiology of Serbia, Belgrade)

Digitally reconstructed radiograph (DRR) is created by computer program transforming the CT slices into a radiograph image. DRR represents the referent image to which the later portal films of treatment field position are compared. (Figure 4.)

Dose-volume-histogram (DVH) is also created and it shows the percent of prescribed dose to every delineated structure. For organs at risk the ALARA principle (as low as reasonably achievable) is recommended following the tolerant dose of each organ. But, although DVH gives valuable information on the dose to each structure, it is calculated on a single pretreatment pelvic organs position, and they are mobile. That is the reliability on a single pretreatment DVH is limited, and does not have to correlate with late toxicity (Fiorino et al., 2009) (Figure 5.)

When the delineation process is completed, the medical physicists arrange beam angles and adjust them to maximize target coverage and minimize high-dose exposure to normal

Fig. 3. Field arrangement for four-field (box) treatment (With thanks to the Institute for

Digitally reconstructed radiograph (DRR) is created by computer program transforming the CT slices into a radiograph image. DRR represents the referent image to which the later

Dose-volume-histogram (DVH) is also created and it shows the percent of prescribed dose to every delineated structure. For organs at risk the ALARA principle (as low as reasonably achievable) is recommended following the tolerant dose of each organ. But, although DVH gives valuable information on the dose to each structure, it is calculated on a single pretreatment pelvic organs position, and they are mobile. That is the reliability on a single pretreatment DVH is limited, and does not have to correlate with late toxicity (Fiorino et al.,

organs. (Choe & Liauw, 2010) (Figure 3.)

oncology and radiology of Serbia, Belgrade)

2009) (Figure 5.)

portal films of treatment field position are compared. (Figure 4.)

Fig. 4. Digitaly reconstructed radiographs (DRR) for AP (a) and right lateral (b) field (With thanks to the Institute for oncology and radiology of Serbia, Belgrade)

Fig. 5. Dose-volume-histogram (DVH) showing the doses delivered to each delineated structure (With thanks to the Institute for oncology and radiology of Serbia, Belgrade)

These new technologies are still under investigation, but first results are optimistic. (Choe & Liauw, 2010) When IGRT is used prostate displacement caused by rectal distension is

Radiation-induced complications can be acute and late. Acute adverse events occur during treatment and late may develop months to years after treatment. When we irradiate the prostate, acute and late toxicity are a consequence of high dose given to the surrounding organs i.e. bladder, rectum and skin. The severance of these side-effects largely depends on

During conventional radiotherapy of the prostate acute toxicity include acute proctitis followed by rectal discomfort, tenesmus and diarrhea, and rarely rectal bleeding. It is mostly mild and resolves after symptomatic therapy with hydration and antidiarrheal and anti-inflammatory medication. Skin reactions include erythema, dry and humid desquamation. According to RTOG scale (RTOG, 1999) acute toxicity has four grades of

Grade 0 1 2 3 4

Moderate erytherma or incipient moist desquamation, mild skid edema

Abdominal pain, mucus and/or blood in stool

4-6 stools per day, night stools

Moderate dysuria that need

symptomatic therapy

Confluent moist

desquamation more than 1.5 cm of the skin, moderate edema

Abdominal pain, fever, peritoneal signs or ileus

More than 7 stools per day and/or incontinency or parentheral substitution due to dehydrations

Symptoms not relieved on symptomatic therapy

Ulcerations or skin necrosis

Perforation

Hemodynamic collapse

**2.6 Acute and late toxicity of external-beam radiotherapy in prostate cancer** 

the tissue volume irradiated and relates to the treatment technique.

Mild erythema

desquamation

Up to 4 stools per day

Table 1. Acute toxicity in radical radiotherapy of prostate cancer-RTOG scale

or dry

complications Asymptomatic

complications Mild dysuria

largely corrected. (Hayden et al., 2010)

severity stated in table 1.

complications

complications

No

Dermatitis No

Colitis No

Diarrhea No

Cystitis, dysuria

According to EAU guidelines in prostate cancer in 2010, for external radiotherapy, a dose of at least 74Gy to PTV is recommended for low-risk prostate cancer because the biochemical disease-free survival is significantly higher when compared to a dose of under 72Gy (69% vs. 63%; P=0.046). For intermediate-risk prostate cancer the dose is ranging from 76Gy to 81Gy, and for high-risk prostate cancer a combination with androgen deprivation is recommended regardless dose escalation since the risk of systemic relapse has to be covered. (Heidenereich et al., 2011)

The patient is treated daily, 1.8 to 2Gy per fraction, on linear accelerator in a position that matches the position taken during CT simulation. The correct position is obtained by immobilizing devices and by setting up the skin tattoo markers to treatment room wall lasers. Once the radiotherapy has started, portal films of arranged fields are taken on the accelerator, in treatment position and compared with digitally reconstructed radiograph (DRR) for set-up or other errors several times during radiotherapy course.
