**2.4 Intensity-modulated radiotherapy (IMRT)**

Intensity-modulated radiotherapy is considered a grate improvement in radiation oncology. It is a form of 3D-CRT in which the optimization of the dose prescribed to the target volume is achieved by x-ray beam intensity changes. By using computer algorithms the intensity of the beam is changed in order to increase the dose difference between the target volume and organs at risk.

Radiotherapy treatment planning using IMRT is based on a CT slices on which the physician delineates target volumes as for the 3D-CRT, as well as organs at risk. For each delineated structure the tolerant dose in imputed in the mathematical algorithms and than the beam intensity is calculated as a function of beam angle. The beam angle is individually adjusted by inclination of the radiotherapy bed, collimator or gentry. (Valicenti et al., 2000) Unlike 3D-CRT, in IMRT the dose from each beam is not delivered all at once. At each beam angle, the intensity of the beam is modulated by multiple smaller subfields that change in time. This allows a high degree of dose conformity around complex and irregularly shaped tumors (Choe & Liauw, 2010) and dose escalation up to 86Gy. (Zelefsky et al., 2002)

#### **2.5 Organ motion tracking and image-guided radiotherapy (IGRT)**

Highly conformal radiation therapy requires precise localization of the prostate. Since the prostate gland is a movable organ due to breathing and distention of rectum and bladder, a variety of strategies have been developed to account prostate motion including transabdominal ultrasound-based imaging, on-line CT and implantation of radiopaque markers.

The prostate gland can not be visualized on portal images, but radiopaque fiducial markers can be placed within the prostate. These markers can be visualized on portal imaging so prior to every treatment a correction of targeting can be made. (Choe & Liauw, 2010) A minimum of three markers should be implanted under ultrasound guidance in the ipsilateral apex, base and contra-lateral mid-gland one week prior to simulation. (Hayden et al., 2010) This technique is used to track interfraction movement (prostate movement between treatments), but it cannot account prostate movement during treatment (intrafractional movement). Nowadays there is a growing interest in real-time tracking of the prostate. There is a special system that uses a real-time tracking of the radiofrequency transponders implanted into the prostate and if they present outside of the predetermined margins the radiation stops.

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

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

Intensity-modulated radiotherapy is considered a grate improvement in radiation oncology. It is a form of 3D-CRT in which the optimization of the dose prescribed to the target volume is achieved by x-ray beam intensity changes. By using computer algorithms the intensity of the beam is changed in order to increase the dose difference between the target volume and

Radiotherapy treatment planning using IMRT is based on a CT slices on which the physician delineates target volumes as for the 3D-CRT, as well as organs at risk. For each delineated structure the tolerant dose in imputed in the mathematical algorithms and than the beam intensity is calculated as a function of beam angle. The beam angle is individually adjusted by inclination of the radiotherapy bed, collimator or gentry. (Valicenti et al., 2000) Unlike 3D-CRT, in IMRT the dose from each beam is not delivered all at once. At each beam angle, the intensity of the beam is modulated by multiple smaller subfields that change in time. This allows a high degree of dose conformity around complex and irregularly shaped

Highly conformal radiation therapy requires precise localization of the prostate. Since the prostate gland is a movable organ due to breathing and distention of rectum and bladder, a variety of strategies have been developed to account prostate motion including transabdominal ultrasound-based imaging, on-line CT and implantation of radiopaque

The prostate gland can not be visualized on portal images, but radiopaque fiducial markers can be placed within the prostate. These markers can be visualized on portal imaging so prior to every treatment a correction of targeting can be made. (Choe & Liauw, 2010) A minimum of three markers should be implanted under ultrasound guidance in the ipsilateral apex, base and contra-lateral mid-gland one week prior to simulation. (Hayden et al., 2010) This technique is used to track interfraction movement (prostate movement between treatments), but it cannot account prostate movement during treatment (intrafractional movement). Nowadays there is a growing interest in real-time tracking of the prostate. There is a special system that uses a real-time tracking of the radiofrequency transponders implanted into the prostate and if they present outside of the predetermined

tumors (Choe & Liauw, 2010) and dose escalation up to 86Gy. (Zelefsky et al., 2002)

**2.5 Organ motion tracking and image-guided radiotherapy (IGRT)** 

(DRR) for set-up or other errors several times during radiotherapy course.

covered. (Heidenereich et al., 2011)

organs at risk.

markers.

margins the radiation stops.

**2.4 Intensity-modulated radiotherapy (IMRT)** 

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 largely corrected. (Hayden et al., 2010)

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

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 the tissue volume irradiated and relates to the treatment technique.

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 severity stated in table 1.



toxicity grade 2, and Medical research council 33% in dose escalated group. (Al-Mamgani et al., 2008, Dearnaley et al., 2007) These results compare with reports of IMRT treatment with 81Gy (3% of patients experienced late rectal toxicity at grade 2 or grater) and treatment with IGRT with 79.8Gy (12% of patients with grade 2 rectal toxicity). (Hayden et al. 2010) For urinary toxicity none of these trials found significant correlation between late adverse events and radiation dose. Although improved radiotherapy techniques appear to enable dose escalation with less toxicity, the optimal dose that can eradicate the disease without the risk

Following external-beam radiotherapy, long-term clinically assessed local tumor control is good for patients with stage T1 cancers (83% at 15 years), but it is falling to 65-68% for T2 and 44-75% for T3 cancers. Reported incidence of positive biopsy after external-beam radiotherapy vary from 18 to 45% and increases with disease bulk from 15% for T1 disease, to 68-79% for men with T2 and T3 cancers. Regarding biochemical control, Hanks et al. reported a long-term biochemical control in 72% of T1 cancers, falling to 22% and 28% for

PSA level and Gleason score are powerful predictors of outcome. In patients with low Gleason score the rate of biochemical control ranges about 75%, compared to only 18% for Gleason score 7 and 0% for Gleason score 8 or 9. In patients with pretreatment PSA more than 20 ng/ml only 28% remained biochemically free of progression at 4 years in the results

Several randomized controlled trials and one meta-analysis shown that improved biochemical outcomes (biochemical failure free survival) are associated with dose escalation. (Kuban et al., 2008, Al-Mmgani et al., 2008, Dearnaley et al., 2007, Zietman et al., 2010, Viani et al., 2009). Radiation Therapy Oncology Group trials have even shown that higher radiation dose improves disease-specific and overall survival in high-grade prostate cancer. (Valicenti et al., 2000) Despite promising results of dose escalation there are still uncertainties regarding routine application of dose escalation especially. The subgroup of patients that will benefit the most from dose escalation is not clearly defined. These trials enrolled men in all risk groups of localized prostate. Only U.K. Medical Research Council trial divided patients in risk groups showing the benefit of dose escalation in all groups. But statistically significance was reached only in high-risk group. In the Dutch trial the benefit from dose escalation from 68 to 78Gy was also registered in intermediate and high-risk patients. These results led to a question whether a higher dose is required for low-risk prostate cancer. Although MD Anderson trial shown the benefit form dose escalation in high-risk group of patients, it also reported longer follow-up of 8.7 years that can indirectly demonstrate a benefit of dose escalation even in the low-risk group. While the improved biochemical outcomes are practically proven with dose escalation, there is still no sufficient evidence of improvement in cancer-specific survival and overall

Regarding overall survival, radiotherapy is efficient method for many cases of localized prostate cancer. Five-year overall survival for T1 and T2 stage ranges about 70-80%, and 90% of local tumor control. Locally advanced stages have poorer prognosis with 5-year overall survival of 40-50%. High Gleason score is the most significant negative prognostic marker

of toxicity is jet to be defined. (Choe & Liauw, 2010)

**2.7 Results of external-beam radiotherapy of prostate cancer** 

bulky T2 and T3 cancers in a mean follow-up of 12.6 years.

of Hanks et al (Dearnaley, 2001)

survival. (Choe & Liauw, 2010)

The most frequent adverse event on the urinary tract is radiation cystitis producing dysuria, nocturia, frequency and urgency. It is low graded in most cases (7.7%) while severe urinary complications are seen in less than 0.5% of patients. According to RTOG study on over 1000 prostate cancer patients treated with external-beam radiotherapy, acute toxicity occurs in 70- 90% of the patients with mild symptoms. Moderate symptoms are developed in 20-45% of the patients while 1-4% has severe or prolonged reactions. (Dearnaley, 2001)

Although acute toxicity is very unpleasant for the patient it usually resolves after the treatment. Late toxicity is of much more concern since it is unpredictable and very often irreversible. According to RTOG, late toxicity also has four grades of severity (table 2).

Mostly it is mild and does not influence quality of life, but sever late toxicity is reported in 4- 8% of patients. Most common genitourinary side effects are chronic cystitis (5%), incontinency, urethral stricture (5%, mostly patients with previous transurethral resection of the prostate), bladder ulceration and impotency (30-40%). Late toxicity on rectum affects 3% of the patients and includes tenesmus, sphincter dysfunction, occasional bleeding, strictures or ulcerations. (Dearnaley, 2001)


Table 2. Late toxicity in radical radiotherapy of prostate cancer-RTOG scale

Introducing 3D-CRT and IMRT the volume of bladder and rectum irradiated is limited, but the dose escalation can still induce significant toxicity. In trials of dose escalation, reported rates of acute toxicity are very similar to those of conventional radiotherapy. Late toxicity however is still considered high. MD Anderson trial has shown a significant gastrointestinal toxicity (grade 2 or more) in 25% of patients with escalated dose comparing to 13% in low dose group (78Gy vs. 70Gy). (Kuban et al., 2008) The Dutch trial reported 26% of late rectal

The most frequent adverse event on the urinary tract is radiation cystitis producing dysuria, nocturia, frequency and urgency. It is low graded in most cases (7.7%) while severe urinary complications are seen in less than 0.5% of patients. According to RTOG study on over 1000 prostate cancer patients treated with external-beam radiotherapy, acute toxicity occurs in 70- 90% of the patients with mild symptoms. Moderate symptoms are developed in 20-45% of

Although acute toxicity is very unpleasant for the patient it usually resolves after the treatment. Late toxicity is of much more concern since it is unpredictable and very often irreversible. According to RTOG, late toxicity also has four grades of severity (table 2). Mostly it is mild and does not influence quality of life, but sever late toxicity is reported in 4- 8% of patients. Most common genitourinary side effects are chronic cystitis (5%), incontinency, urethral stricture (5%, mostly patients with previous transurethral resection of the prostate), bladder ulceration and impotency (30-40%). Late toxicity on rectum affects 3% of the patients and includes tenesmus, sphincter dysfunction, occasional bleeding, strictures

Grade 0 1 2 3 4

Diffuse

teleangiectasia, macroscopic hemathuria

Moderate skin atrophy, teleangiectasis, total hair loss

Moderate diarrhea, abdominal pain, rectal mucus or harder bleeding

Introducing 3D-CRT and IMRT the volume of bladder and rectum irradiated is limited, but the dose escalation can still induce significant toxicity. In trials of dose escalation, reported rates of acute toxicity are very similar to those of conventional radiotherapy. Late toxicity however is still considered high. MD Anderson trial has shown a significant gastrointestinal toxicity (grade 2 or more) in 25% of patients with escalated dose comparing to 13% in low dose group (78Gy vs. 70Gy). (Kuban et al., 2008) The Dutch trial reported 26% of late rectal

Frequent urinating, dysuria and hemathuria, bladder capacity less than 150 ml

Severe skin atrophy, severe teleangiectasia

Ileus or bleeding that requires surgical treatment

Bladder necrosis, capacity less than 100 ml, hemorrhagic cystitis

Ulceration

Necrosis, perforation, fistula

Mild epithelia atrophy, discreet teleangiectasia

Mild skin atrophy, hyperpigment ation, hair loss

Mild diarrhea or increased bowel motion, or mild rectal bleeding

Table 2. Late toxicity in radical radiotherapy of prostate cancer-RTOG scale

the patients while 1-4% has severe or prolonged reactions. (Dearnaley, 2001)

or ulcerations. (Dearnaley, 2001)

complications

complications

complications

Bladder No

Skin No

Bowels No

toxicity grade 2, and Medical research council 33% in dose escalated group. (Al-Mamgani et al., 2008, Dearnaley et al., 2007) These results compare with reports of IMRT treatment with 81Gy (3% of patients experienced late rectal toxicity at grade 2 or grater) and treatment with IGRT with 79.8Gy (12% of patients with grade 2 rectal toxicity). (Hayden et al. 2010) For urinary toxicity none of these trials found significant correlation between late adverse events and radiation dose. Although improved radiotherapy techniques appear to enable dose escalation with less toxicity, the optimal dose that can eradicate the disease without the risk of toxicity is jet to be defined. (Choe & Liauw, 2010)

#### **2.7 Results of external-beam radiotherapy of prostate cancer**

Following external-beam radiotherapy, long-term clinically assessed local tumor control is good for patients with stage T1 cancers (83% at 15 years), but it is falling to 65-68% for T2 and 44-75% for T3 cancers. Reported incidence of positive biopsy after external-beam radiotherapy vary from 18 to 45% and increases with disease bulk from 15% for T1 disease, to 68-79% for men with T2 and T3 cancers. Regarding biochemical control, Hanks et al. reported a long-term biochemical control in 72% of T1 cancers, falling to 22% and 28% for bulky T2 and T3 cancers in a mean follow-up of 12.6 years.

PSA level and Gleason score are powerful predictors of outcome. In patients with low Gleason score the rate of biochemical control ranges about 75%, compared to only 18% for Gleason score 7 and 0% for Gleason score 8 or 9. In patients with pretreatment PSA more than 20 ng/ml only 28% remained biochemically free of progression at 4 years in the results of Hanks et al (Dearnaley, 2001)

Several randomized controlled trials and one meta-analysis shown that improved biochemical outcomes (biochemical failure free survival) are associated with dose escalation. (Kuban et al., 2008, Al-Mmgani et al., 2008, Dearnaley et al., 2007, Zietman et al., 2010, Viani et al., 2009). Radiation Therapy Oncology Group trials have even shown that higher radiation dose improves disease-specific and overall survival in high-grade prostate cancer. (Valicenti et al., 2000) Despite promising results of dose escalation there are still uncertainties regarding routine application of dose escalation especially. The subgroup of patients that will benefit the most from dose escalation is not clearly defined. These trials enrolled men in all risk groups of localized prostate. Only U.K. Medical Research Council trial divided patients in risk groups showing the benefit of dose escalation in all groups. But statistically significance was reached only in high-risk group. In the Dutch trial the benefit from dose escalation from 68 to 78Gy was also registered in intermediate and high-risk patients. These results led to a question whether a higher dose is required for low-risk prostate cancer. Although MD Anderson trial shown the benefit form dose escalation in high-risk group of patients, it also reported longer follow-up of 8.7 years that can indirectly demonstrate a benefit of dose escalation even in the low-risk group. While the improved biochemical outcomes are practically proven with dose escalation, there is still no sufficient evidence of improvement in cancer-specific survival and overall survival. (Choe & Liauw, 2010)

Regarding overall survival, radiotherapy is efficient method for many cases of localized prostate cancer. Five-year overall survival for T1 and T2 stage ranges about 70-80%, and 90% of local tumor control. Locally advanced stages have poorer prognosis with 5-year overall survival of 40-50%. High Gleason score is the most significant negative prognostic marker

Strictly speaking, from the point of view of radiobiology, the only differences (not great) in the indications for applying permanent (LDR) or temporary implantation (HDR) are mostly related to tumor grade. For example, with low-grade and low-risk tumors (eg Stage<T2a, PSA<10, Gleason Score 2-4) and slow-growing tumors, we expect greater efficiency in the application of permanent implants, while with tumors of high grade and higher risk, higher efficiency is expected from temporary implantation. Although there are relative differences in the indications for application of LDR or HDR brachytherapy, it seems that the predominant technique is the one with permanent implants (LDR). Selection of isotopes (125I or 103Pd) is in the favor of the cheaper iodine, so if otherwise not indicated it's considered that radioisotope 125I is being used in LDR brachytherapy for treating prostate cancer. Permanent implants are rarely used in cases of rest or local recurrence after prostatectomy or transcutaneous radiotherapy. In this case a HDR brachytherapy with 192Ir of initial

Prostate brachytherapy requires a multidisciplinary approach, which assumes collaboration between urologists, radiation oncologists (brachytherapists), anesthesiologists and brachytherapy physicists. Regardless of which brachytherapy modality is implemented in prostate brachytherapy, and with the aim to providing a top quality treatment, all steps are

1. Assessing the stage and spread of the disease (laboratory-biochemical, prostate morphology / palpatory findings, prostate size - US and TRUS /, histopathological verification and determination of Gleason Score, a CT/MRI, scintigraphy,

2. Assessing the possibility of applications (talk with the patient, the patient's state, maximum urinary flow rate, the presence of residual urine, previous TUR, assessment of cardiovascular conditions, the possibility of implanting, anatomy of the pelvis,

3. Preparing the patient prior to implantation - 24 hours in advance (admission of the patient, medical therapy, anti-coagulant and antibiotic, preparation of the patient,

4. Preparation of instrumentarium (selection and sterilization of instruments, calibration

5. Patient's positioning and anesthesia (in lithotomic position on the movable therapy

6. Placing markers of critical radiosensitive structures (Folly catheter for marking the

7. Setting TRUS probes, template and steper, and prostate visualisation, and visualisation of urethra and rectum (in steps of max. 5 mm from base to apex (Grey et al., 2000),

8. Pre-planning (determinatuion of the number and location of radiation sources and

9. The application (placing the radiation source guides/needles; in the LDR technique

inserting a radiation source - seeds) - TRUS-guided (Figure 8. b)

implantation.

strictly determined:

rectum cleaning)

bladder and urethra)

methods of implantation)

(Figure 7. a, c)

**3.1 Low dose rate brachytherapy** 

activity over 370 GBq, by using afterloading device, is applied.

determination of TNM disease stage)

prostate size, type of implant LDR vs. HDR)

of stepper, network and TRUS ) (Figure 6.)

table; spinal or general anesthesia)

half-life of 74.2 days, mean photon energy of about 380keV,) - a temporary

since it is associated with higher malignant potential. Cancer related death for high Gleason score tumors (8-10) is about 60-80% in 15 years. (Hadzi-Djokic, 2005)
