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

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

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

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

distant metastases and longer progression free survival in hormone therapy-radiotherapy

Local

>24m vs. 0 + 53 vs. 20

4m vs. 0 + 33 vs. 21

36m vs. 0 + 85 vs. 48

28m vs. 0 +

Bolla M. recommends concomitant and adjuvant hormone therapy for three years in combination with radiotherapy for patients with locally advanced, intermediate or high-risk

Although it is shown that androgen deprivation before, concomitantly and/or after radiotherapy significantly improves local disease control, minimizes progression and prolongs overall survival in locally advanced prostate cancer on intermediate and high-risk, there is not enough evidence for recommendation of optimal time to start hormone therapy, the type of hormones and the duration of the treatment which in clinical trials lasts from 3

For patients in which prostate cancer develops quickly with bony and/or other metastases and elevation of PSA, androgen deprivation is considered a therapeutic method of choice. It includes orchyectomy or TAB. Radiotherapy is considered only as palliative for painful

Radiotherapy of bony metastases is mostly performed as local therapy to involved bones but sometimes it can be applied as half-body or total-body irradiation. For solitary or

control PFS (%) OS

p<0.0001

p=0.004

p<0.001

46.4 vs. 28.1 p<0.001

4m vs. 4m + NA NA 4 years

(%) Follow-up

5 years

5 years

5 years

Gs 8-10 66 vs. 55 p=0.03

Gs 2-6 70 vs. 52 p=0.015

79 vs. 62

Gs 8-10 81 vs. 70.7 p=0.044

p=0.01 5 years

duration

group. (Jelić et al., 2005) (Table 4.)

N+,T3

T4

T4

prostate cancer. (Bolla, 2003)

months to 3 years. (ESMO, 2003)

RTOG

RTOG

EORTC

RTOG

RTOG

85-31 977 T1-T2,

86-10 456 T2-T4

<sup>22863</sup>415 T1-T4

92-02 <sup>1554</sup> T2c-

94-13 <sup>1323</sup> T1c-

N Stage Therapy Therapy

Adj vs. only RT

Neoadj/conc vs. only RT

> conc/adj vs. only RT

Neoadj/conc /adj vs. Neoadj/conc

> Neoadj vs. adj

Table 4. Hormone therapy and RT. Randomized studies

**6. Radiotherapy in metastatic prostate cancer** 

bony metastases or threatening pathological fracture.

realizing hormone agonist) or by direct blockade of androgen receptors with androgen antagonists. (Anderson, 2003) Although, it is generally thought that androgen deprivation combined with radiotherapy influence the results of treatment in local and systemic way, it is uncertain whether that action is the result of radiosensitizing, systemic micro metastases eradication or both. Androgen deprivation leads to the shrinkage of the entire prostate gland reducing the irradiated volume to which the higher dose can be applied. In several studies this prostate shrinkage is ranging form 30% to 40%. Some authors say that it improves radiotherapy effectiveness by oxygenation of hypoxic cancer cells and that it even induces apoptosis and tumoricidal immune system response.


Table 3. 10 and 15-year survival rate for patients with locally advanced prostate cancer treated with radical RT

The role of androgen deprivation therapy is unclear in men with low risk prostate cancer but some patients still received it as primary or neoadjuvant treatment. The Radiation Therapy Oncology Group (RTOG) 94-08 randomized trial included almost 2000 men with T1b-T2 prostate cancer and PSA less than 20ng/ml. Androgen deprivation therapy was administered 4 months prior or concomitantly with radiotherapy. Overall survival at 8 years was 76% vs. 73% for combined treatment and radiotherapy only, respectively. The diseasespecific survival was 98% for hormone and irradiation vs. 99% for radiotherapy alone. This study did not bring solid results, as well as many others, because some patients were clinically in a higher risk stage than deemed low risk according to National Comprehensive Network classification. Retrospective studies of Bolla et al. and Cietzki at al. are among few that have shown the advantage of radiotherapy combine with androgen-deprivation in low risk prostate cancer (Milecki et al., 2010)

For intermediate and high-risk patients many randomized studies were performed such as RTOG 85-31 (977 patients T1-T2, T3, N+, adjuvant hormone therapy vs. radiotherapy alone), RTOG 86-10 (456 patients, T2-T4, neoadjuvant/concomitant hormone therapy for 4 months vs. radiotherapy alone), EORTC 22863 (415 patients, T1-T4 prostate cancer, concomitant/adjuvant hormone therapy for 36 months vs. radiotherapy alone). In 5-years follow-up all of them have shown a statistically significant difference in improved local disease control, reduction of

realizing hormone agonist) or by direct blockade of androgen receptors with androgen antagonists. (Anderson, 2003) Although, it is generally thought that androgen deprivation combined with radiotherapy influence the results of treatment in local and systemic way, it is uncertain whether that action is the result of radiosensitizing, systemic micro metastases eradication or both. Androgen deprivation leads to the shrinkage of the entire prostate gland reducing the irradiated volume to which the higher dose can be applied. In several studies this prostate shrinkage is ranging form 30% to 40%. Some authors say that it improves radiotherapy effectiveness by oxygenation of hypoxic cancer cells and that it even

(%)

15 Year Survival (%)

induces apoptosis and tumoricidal immune system response.

treated with radical RT

risk prostate cancer (Milecki et al., 2010)

Study/Institution Clinical T stage 10 Year Survival

Pattern of Care T3-T4 33 23

Stanford T3 35 18

Stanford T4 15 15

M.D. Anderson T3 45 31

Table 3. 10 and 15-year survival rate for patients with locally advanced prostate cancer

The role of androgen deprivation therapy is unclear in men with low risk prostate cancer but some patients still received it as primary or neoadjuvant treatment. The Radiation Therapy Oncology Group (RTOG) 94-08 randomized trial included almost 2000 men with T1b-T2 prostate cancer and PSA less than 20ng/ml. Androgen deprivation therapy was administered 4 months prior or concomitantly with radiotherapy. Overall survival at 8 years was 76% vs. 73% for combined treatment and radiotherapy only, respectively. The diseasespecific survival was 98% for hormone and irradiation vs. 99% for radiotherapy alone. This study did not bring solid results, as well as many others, because some patients were clinically in a higher risk stage than deemed low risk according to National Comprehensive Network classification. Retrospective studies of Bolla et al. and Cietzki at al. are among few that have shown the advantage of radiotherapy combine with androgen-deprivation in low

For intermediate and high-risk patients many randomized studies were performed such as RTOG 85-31 (977 patients T1-T2, T3, N+, adjuvant hormone therapy vs. radiotherapy alone), RTOG 86-10 (456 patients, T2-T4, neoadjuvant/concomitant hormone therapy for 4 months vs. radiotherapy alone), EORTC 22863 (415 patients, T1-T4 prostate cancer, concomitant/adjuvant hormone therapy for 36 months vs. radiotherapy alone). In 5-years follow-up all of them have shown a statistically significant difference in improved local disease control, reduction of

RTOG 75-06 T3-T4 38 No results

Mallinckrodt T3 38 No results



Table 4. Hormone therapy and RT. Randomized studies

Bolla M. recommends concomitant and adjuvant hormone therapy for three years in combination with radiotherapy for patients with locally advanced, intermediate or high-risk prostate cancer. (Bolla, 2003)

Although it is shown that androgen deprivation before, concomitantly and/or after radiotherapy significantly improves local disease control, minimizes progression and prolongs overall survival in locally advanced prostate cancer on intermediate and high-risk, there is not enough evidence for recommendation of optimal time to start hormone therapy, the type of hormones and the duration of the treatment which in clinical trials lasts from 3 months to 3 years. (ESMO, 2003)
