**3.1.1 Results of low dose rate brachytherapy**

Prostate cancer with its characteristics and different biological behavior represents a problem in the analysis of brachytherapy final outcomes in terms of overall survival or local control. We are aware that many patients with untreated prostate cancer can survive tens of years, ie. do not die from prostate cancer. Therefore to evaluate the effectiveness of treatment of patients with prostate cancer, as for overall survival and local control, the PSA level was adopted.

Greem and associates (Greem et al., 1997 )provide representation of the results of treatment of patients with permanent implants (monotherapy), showing a five-year survival of NED (no evidence of disease) of 94%, 84% and 54% for low risk, medium risk and higher risk

Soon, the advantages of HDR regime compared to LDR brachytherapy of prostate cancer were noticed, which are reflected in: the high precision of application, the possibility of subsequent dose optimization, more accurate dose planning and application, sparing the surrounding tissues and organs, more favorable radiobiological effect, the fact that after treatment there are no sources of radiation in the patient and therefore no possibility of source "seeds" migration into the bladder, rectum or surrounding larger blood vessels, there is no irradiation of staff, there is the possibility of extending indicational scope of application and easier possibility of combination with transcutaneous radiotherapy. However, when it comes to temporary HDR brachytherapy of prostate cancer as monotherapy, less obvious results and experiences are presented in the literature, so one can get the wrong impression that this modality of brachytherapy is either less efficient or at very least, least mystified. To clarify this problem to an extent, if not totally resolve, the association of American Brachytherapy Society has formed a High-Dose Rate Task Group (Hsu, C., Yamada, Y., Vigneaut, E., Pouliout, J.) with the aim to define general criteria for inclusion of patients with prostate cancer in the treatment group Temporary implants (HDR), which was formed following the general criteria for inclusion: clinical stageT1-T3 and selected T4, Gleason Score any, PSA no upper limit, no distant metastases (T1-3N0M0). Criteria for relative exclusion are: severe urinary obstruction, extensive TUR defects, the TUR within 6 months, vascular disease. Absolute contraindications are impossibility to

Given all the above-mentioned recommendations, for inclusion and exclusion, and in particular those given by the American Brachytherapy Society, extended operational criteria and opinions can be formed related to the application of HDR brachytherapy in different patient groups, including recommendations on the total dose and method of its fractions,

 monotherapy - with tumor stage T1-T2 N0 M0, Gleason Score <7 and prostate volume to 70 cc and T3 confined to the prostate (TD - 31.5 Gy/3 fr. To TD45/6 hypofractioned (Duchesne & Peters, 1999) or hyperfractioned / pause between the fraction of at least 6 hours or even up to 54Gy/9 fr./5 days (Yoshioka et al., 2006) (where the stage T3 N0

boost in the combined radiotherapy approach (TD - 12 (Mate et al., 1998) -24 (Demanes

for recurrent disease confined to the prostate (depending on the previousl therapy TD>

Yoshioka et al (Yoshioka et al., 2006) presented the results of 111 patients (15 low, 28 medium and 68 high risk, according to the ASTRO criteria (ASTRO, 1997) treated with HDR temporary implantation (monotherapy), showing a three-year and five-year survival without signs of biochemical disease of 83% and 70%, and overall survival of 100% and 97%, respectively. For the 17 patients from high risk groups, in which biochemical relapse was observed, in 9 patients the presence of distant metastases were confirmed, of which 4 patients died. Given that this group of patients is not stratified based on risk, it is clear that the shown results after the HDR brachytherapy are comparable or even better than in patients treated with permanent implants (monotherapy) (Blasko et al., 2000, Beyer, 2001,

et al., 2009) Gy/1-4 fr. EBRT ± 36-50Gy or 9-15Gy/1-2 fr. EBRT ± 65Gy );

further: to have no contraindications (no indication for exclusion).

anesthesia and no possibility of peaceful lying

M0 may include seminal vessicles);

**3.2.1 Results of high dose rate brachytherapy** 

Gy/1-2 7-14 fr. to 8Gy/4 fr.)

Greem et al., 1997).

and as:

group of 403 patients, respectively . Blasko and associates (Blasko et al, 2000) show the results of a five-year biochemical PSA control: 94%, 82% and 65% for low risk, medium risk and higher risk respectively. Slightly worse, but comparable results are displayed by other authors: 85-94%, 33-82% and 5-65% for low risk, medium risk and high-risk group, respectively (Beyer, 2001). Based on these results, most urologists and brachytherapists exclude a group of patients at high risk from the LDR brachytherapy and consider them patients with advanced disease in which the tumor penetrated the prostate capsule. Association of American Brachytherapy Society has established a Low Dose-Rate Task Group (Merrick, G., Zelefsky, M., Sylvester, E., Nag, S., Bice, W) with the task of defining the general criteria for inclusion of patients with prostate cancer in the group for the treatment by permanent implants (LDR): expected survival > 5 years, clinical stage T1b-T2c and selected T3, Gleason Score<10, PSA<50ng/ml, without involved lymph nodes, no distant metastases, Karnofsky performance status> 70%. Criteria for exclusion are: inflammatory prostate disease, severe urinary obstruction, the middle lobe hyperplasia, extensive TUR defects, a prostate size greater than 60x50 mm, the extension of disease to the seminal vesicles and bladder, involved lymph nodes, previously conducted EBRT. Absolute contraindications are distant metastatic disease, the inability of anesthesia (general, spinal, epidural), no possibility of peaceful lying, expected survival <5 years.

It is obvious that the consistent application of these criteria for inclusion and exclusion would ensure consistent application of LDR brachytherapy in this roup of patients, with the results of treatment (five-and even ten-year PSA control NED> 85%).

#### **3.1.2 Toxicity of low dose rate brachtherapy**

Mild and transient acute urinary symptoms (LENT SOMA, 1995) (hematuria and dysuria grade G1-G2) often accompany LDR brachytherapy, while the acute symptoms on the rectum (proctitis, tenesms and bleeding) are rare and mainly a result of edema and hematoma. All of the symptoms can be associated to radiation or trauma during the application procedure.

As late symptoms of bladder neck irradiation, chronic irritative urinary symptoms may occur and in a small number of cases due to urethral scarring, obstruction or incontinence may occur. Late effects on the rectum are mild, and manifested by periodic bleeding and proctitis. Erectile function was preserved for over 70% of treated patients whose erectile function was satisfactory before the implementation of brachytherapy. In order to preserve erectile function, it is important to avoid positioning of seeds in the perineal area, outside the prostate apex, which prevents the occurrence of fibrosis and consequent devascuralisation of this region. Most patients (over 2/3) treated with permanent implants, estimate their quality of life as good, which is just as important as biochemical and clinical course of disease.

However, due to the relatively limited fixation of radioactive seeds (which are smooth on the surface) there is a possibility of their inter-prostate migration and the creation of "hot" and "cold" zones, as well as, their migration to other organs (rectum, bladder and pelvic veins and even lungs), which sometimes requires serious surgical treatment and drastically reduces the quality of patient's life.

#### **3.2 High dose rate brachytherapy**

HDR temporary prostate cancer brachytherapy with 192Ir entered into clinical practice mainly in combination with transcutaneous radiotherapy about 20 years ago. Obviously, it was necessary to acquire certain technical and technological advances for its application

group of 403 patients, respectively . Blasko and associates (Blasko et al, 2000) show the results of a five-year biochemical PSA control: 94%, 82% and 65% for low risk, medium risk and higher risk respectively. Slightly worse, but comparable results are displayed by other authors: 85-94%, 33-82% and 5-65% for low risk, medium risk and high-risk group, respectively (Beyer, 2001). Based on these results, most urologists and brachytherapists exclude a group of patients at high risk from the LDR brachytherapy and consider them patients with advanced disease in which the tumor penetrated the prostate capsule. Association of American Brachytherapy Society has established a Low Dose-Rate Task Group (Merrick, G., Zelefsky, M., Sylvester, E., Nag, S., Bice, W) with the task of defining the general criteria for inclusion of patients with prostate cancer in the group for the treatment by permanent implants (LDR): expected survival > 5 years, clinical stage T1b-T2c and selected T3, Gleason Score<10, PSA<50ng/ml, without involved lymph nodes, no distant metastases, Karnofsky performance status> 70%. Criteria for exclusion are: inflammatory prostate disease, severe urinary obstruction, the middle lobe hyperplasia, extensive TUR defects, a prostate size greater than 60x50 mm, the extension of disease to the seminal vesicles and bladder, involved lymph nodes, previously conducted EBRT. Absolute contraindications are distant metastatic disease, the inability of anesthesia (general, spinal,

It is obvious that the consistent application of these criteria for inclusion and exclusion would ensure consistent application of LDR brachytherapy in this roup of patients, with the

Mild and transient acute urinary symptoms (LENT SOMA, 1995) (hematuria and dysuria grade G1-G2) often accompany LDR brachytherapy, while the acute symptoms on the rectum (proctitis, tenesms and bleeding) are rare and mainly a result of edema and hematoma. All of the symptoms can be associated to radiation or trauma during the application procedure. As late symptoms of bladder neck irradiation, chronic irritative urinary symptoms may occur and in a small number of cases due to urethral scarring, obstruction or incontinence may occur. Late effects on the rectum are mild, and manifested by periodic bleeding and proctitis. Erectile function was preserved for over 70% of treated patients whose erectile function was satisfactory before the implementation of brachytherapy. In order to preserve erectile function, it is important to avoid positioning of seeds in the perineal area, outside the prostate apex, which prevents the occurrence of fibrosis and consequent devascuralisation of this region. Most patients (over 2/3) treated with permanent implants, estimate their quality of life as good, which is just as important as biochemical and clinical

However, due to the relatively limited fixation of radioactive seeds (which are smooth on the surface) there is a possibility of their inter-prostate migration and the creation of "hot" and "cold" zones, as well as, their migration to other organs (rectum, bladder and pelvic veins and even lungs), which sometimes requires serious surgical treatment and drastically

HDR temporary prostate cancer brachytherapy with 192Ir entered into clinical practice mainly in combination with transcutaneous radiotherapy about 20 years ago. Obviously, it was necessary to acquire certain technical and technological advances for its application

epidural), no possibility of peaceful lying, expected survival <5 years.

results of treatment (five-and even ten-year PSA control NED> 85%).

**3.1.2 Toxicity of low dose rate brachtherapy** 

course of disease.

reduces the quality of patient's life.

**3.2 High dose rate brachytherapy** 

Soon, the advantages of HDR regime compared to LDR brachytherapy of prostate cancer were noticed, which are reflected in: the high precision of application, the possibility of subsequent dose optimization, more accurate dose planning and application, sparing the surrounding tissues and organs, more favorable radiobiological effect, the fact that after treatment there are no sources of radiation in the patient and therefore no possibility of source "seeds" migration into the bladder, rectum or surrounding larger blood vessels, there is no irradiation of staff, there is the possibility of extending indicational scope of application and easier possibility of combination with transcutaneous radiotherapy. However, when it comes to temporary HDR brachytherapy of prostate cancer as monotherapy, less obvious results and experiences are presented in the literature, so one can get the wrong impression that this modality of brachytherapy is either less efficient or at very least, least mystified. To clarify this problem to an extent, if not totally resolve, the association of American Brachytherapy Society has formed a High-Dose Rate Task Group (Hsu, C., Yamada, Y., Vigneaut, E., Pouliout, J.) with the aim to define general criteria for inclusion of patients with prostate cancer in the treatment group Temporary implants (HDR), which was formed following the general criteria for inclusion: clinical stageT1-T3 and selected T4, Gleason Score any, PSA no upper limit, no distant metastases (T1-3N0M0). Criteria for relative exclusion are: severe urinary obstruction, extensive TUR defects, the TUR within 6 months, vascular disease. Absolute contraindications are impossibility to anesthesia and no possibility of peaceful lying

Given all the above-mentioned recommendations, for inclusion and exclusion, and in particular those given by the American Brachytherapy Society, extended operational criteria and opinions can be formed related to the application of HDR brachytherapy in different patient groups, including recommendations on the total dose and method of its fractions, and as:


#### **3.2.1 Results of high dose rate brachytherapy**

Yoshioka et al (Yoshioka et al., 2006) presented the results of 111 patients (15 low, 28 medium and 68 high risk, according to the ASTRO criteria (ASTRO, 1997) treated with HDR temporary implantation (monotherapy), showing a three-year and five-year survival without signs of biochemical disease of 83% and 70%, and overall survival of 100% and 97%, respectively. For the 17 patients from high risk groups, in which biochemical relapse was observed, in 9 patients the presence of distant metastases were confirmed, of which 4 patients died. Given that this group of patients is not stratified based on risk, it is clear that the shown results after the HDR brachytherapy are comparable or even better than in patients treated with permanent implants (monotherapy) (Blasko et al., 2000, Beyer, 2001, Greem et al., 1997).

After radical prostatectomy, the application of radiotherapy can lower the incidence of local relapses, but its effect on distant metastases appearance is not confirmed. Alternative regimen is the use of androgen-deprivation therapy alone or in combination with radiotherapy which can also improve local control and eradication of distant metastases.

Three randomized trials (Bolla, Wiegel & Thompson), have shown an advantage in biochemical relapse-free survival with postoperative radiotherapy for men with positive surgical margins or pT3 disease. These trials compared postoperative radiotherapy with 60- Gy to the prostatic fossa to radical prostatectomy alone in men with high-risk prostate cancer. With the use of postoperative irradiation the 5-year biochemical progression-free survival was significantly improved, as well as clinical progression-free survival. Thompson's trial has also show an advantage of overall survival (10.3 years for irradiated patients after prostatectomy to 3.1 year for prostatectomy only). Bolla failed to demonstrate this advantage. That means that not all men with adverse prognostic factors will relapse. Also, not all men treated with postoperative radiotherapy will be cured. Combined treatment is also associated with greater toxicity than radiotherapy or prostatectomy alone. So what will the optimal treatment be? (Hayden et al., 2010, Bolla et al., 2005, Wiegel et al., 2009, Thompson et al., 2009) Eastham et al. managed to give actually 4 possible scenarios for post-prostatectomy setting: (1) there is no residual disease and adjuvant radiation is not necessary; (2) persistent disease is present in the prostatic fossa only and adjuvant irradiation may provide long-term cure; (3) there is a residual local disease as well as microscopic disseminated disease and adjuvant irradiation may eradicate local disease but will have no impact on the systemic component; (4) disease is only systemic and adjuvant

Salvage radiotherapy in the setting of a rising PSA after prostatectomy is unproven and still controversial. This is most likely the result of inadequately selected patients for postprostatectomy irradiation. Many of them already have systemic recurrence so a detail

The special issue is the use of adjuvant hormone therapy. Some studies show that the application of adjuvant hormone therapy reduces the risk of positive surgical margins, improves local disease control, eradicates micro metastases and prolongs time to progression and overall survival. On the other hand, neoadjuvant hormone therapy, prior to surgery, in order to downstage the disease, has not been proven for successes neither in preventing biochemical or clinical relapse nor in improving survival so in most centres it is

**5. Androgen-derprivation therapy combined with radiotherapy of the prostate** 

Radiotherapy is traditionally the treatment of choice in locally advanced prostate cancer. Unfortunately the results of radical radiotherapy regarding 10-years and 15-years overall

Androgen deprivation therapy is used routinely in combination with radiotherapy for locally advanced prostate cancer, but recent studies show that it improves treatment result is

Hormone therapy, that is in fact androgen deprivation, can be realized in several ways: orchyectomy, blockade of the hypothalamus-hypophysis-gonade path (with gonadothropin

(Hadzi-Djokic, 2005)

local irradiation is not necessary.

deserted. (Dearnaley, 2005)

**cancer** 

diagnostic workout is necessary. (Eastham et al., 2010)

survivals are not satisfactory (Zlotecki, 2001) (Table 3.)

localized and intermediate-risk disease.(Milecki et al., 2010).
