**1. Introduction**

Prostate cancer is the leading cancer diagnosis in men, and the second cuase, after lung cancer, of cancer death in men in the U.S. Worldwide is the fourth most common cancer in men with variable incidence and mortality rates, based on geographic regions (1). In Europe is the most common solid tumor, with an incidence of 214 cases per 1000 men, outnumbering the lung and colorectal cancers, and is the second most common cause of cancer death in men.

In recent years, the incidence of prostate cancer is increasing in most countries due to the improvement and widespread use of PSA, aging and probably a real increase in incidence. In men after 40 years there is a progressively incidence increase, with a peak at age 80. The countries with the highest mortality rate for prostate cancer are: Switzerland, Scandinavia and the USA-adjusted death rates by age group between 15-20/100.000 inhabitants. By contrast, the Asian countries with Japan and China leading the way, have the lowest mortality rate (less than 5 per 100,000 population) (1).

The geographic incidence variations of prostate Cancer are multiple and complex, but there are genetic and environmental factors, which seem to be more involved in its genesis. African Americans are those who have higher rates of prostate ca. As mentioned above, China and Japan have lower rates in the incidence of prostate ca and USA one of the highest in the world, well, it is noteworthy that Asian Americans have lower incidence rate of prostate cancer than white Americans, the indicating that the genetic factor is crucial in the development of the disease.

The overall increase in the incidence of prostate cancer worldwide in recent decades, is justified with the development of PSA screening protocols of prostate Cancer. The diagnosis of prostate cancer is based on the determination of serum PSA. The risk of prostate cancer is depending on Serum PSA (2):

> PSA 0-2 ng / ml: 15-25%. PSA 2-4 ng / ml: 17-32% PSA 4-10 ng / ml: 17-32% PSA> 10 ng / ml: 43-65%.

There is still much controversy among health professionals about what is the best protocol for the screening of prostate cancer. The long awaited results of two prospective, randomised trials were published in 2009. The Prostate, Lung, Colorectal, and Ovarian

Radical Prostatectomy in High Risk Prostate Cancer 135

risk prostate cancer are at an increased risk of PSA failure, the need for secondary therapy, metastatic progression and death from prostate cancer. Nevertheless, not all high-risk patients have a uniformly poor prognosis after RP (10). There is no consensus regarding the optimal treatment of men with high-risk prostate cancer. Decisions on whether to elect

**Low risk Intermediate risk High risk** 

As expected, survival and success of the treatment applied in prostate cancer is closely

In this chapter we will focus on Prostate Cancer at high risk as well as the different therapeutic options, focusing on the radical prostatectomy as an effective treatment of the

The factors that best define the high risk prostate cancer are those described by D'Amico (11)

Gleason ≥ 8 points and / or PSA ≥ 20 and / or clinical stage ≥ T2c

These high-risk tumors are at high risk for recurrence, either local or remote, so they are also traditionally called "locally advanced" (12) or "poorly differentiated" (13). If the patient has the 3 items they are considered "very high risk" and have a high probability to die from

Another factor that has been added as a fourth factor is pretreatment *PSA velocity* which if

The simplification of the term "risk" has led many doctors to select patients and improperly included in high-risk groups. Also, following the analysis of these high-risk criteria, we can not quantify the individual risk to a patient, for example, with stage T2c and Gleason 8 would have the same risk that a patient with a PSA 70 and stage T3a (17). That is why this classification system is inadequate and we must use another tool to individualize the risk of each patient; this tool are *Nomograms* which individually allow to analyze and quantify the risk presented by each patient in response to multiple risk factors or variables, integrated in a complex mathematical formula (18). There are plenty of nomograms (19) that have been designed for use in prostate cancer in recent years and could be classified into 3 groups: *Diagnostic nomograms:* those who pretend to estimate the probability of a patient developing prostate cancer. For example, the Vienna nomogram (20) that analyzes the number of

*Staging nomograms*: such as the Partin tables (21), which indicates the likelihood of organconfined disease. Or A. Borque neural network for predicting pathological stage in men

T2c-T3-T4 or PSA > 20 or

Gleason ≥8

surgery as local therapy should be based on the best available clinical evidence.

T2b or PSA 10-20 or

Glesason 7

Table 1. D'Amico classification of patients according to risk group

linked to the stadium and the risk presented by the patient.

approved by the American Urological Association in 2007 are:

greater 2ng/ml/year is included as criteria for high-risk disease (15,16).

**2. Defining high risk prostate cancer** 

cylinders to take a biopsy of the prostate.

undergoing radical prostatectomy. (22)

T1-T2a & PSA<10 y

Gleason ≤6

disease.

prostate cancer (14).

(PLCO) Cancer Screening Trial randomly assigned 76,693 men at 10 US centres to receive either annual screening with PSA and DRE or standard care as the control. After 7 years' follow-up, the incidence of prostate cancer per 10,000 person-years was 116 (2,820 cancers) in the screening group and 95 (2,322cancers) in the control group (rate ratio, 1.22) (3). The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screened group and 1.7 (44 deaths) in the control group (rate ratio, 1.13). The data at 10 years were 67% complete and consistent with these overall findings. The PLCO project team concluded that prostate cancer related mortality was very low and not significantly different between the two study groups. The European Randomized Study of Screening for Prostate Cancer (ERSPC) included a total of 162,243 men from seven countries aged between 55 and 69 years. The men were randomly assigned to a group offered PSA screening at an average of once every 4 years or to an unscreened control group. During a median follow-up of 9 years, the cumulative incidence of prostate cancer was 8.2% in the screened group and 4.8% in the control group (4). The rate ratio for death from prostate cancer was 0.80 in the screened group compared with the control group. The absolute risk difference was 0.71 deaths per 1,000 men. This means that 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer. The ERSPC investigators concluded that PSA-based screening reduced the rate of death from prostate cancer by 20%, but was associated with a high risk of over-diagnosis.

Both trials have received considerable attention and comments. In the PLCO trial, the rate of compliance in the screening arm was 85% for PSA testing and 86% for DRE. However, the rate of contamination in the control arm was as high as 40% in the first year and increased to 52% in the sixth year for PSA testing and ranged from 41% to 46% for DRE. Furthermore, biopsy compliance was only 40-52% versus 86% in the ERSPC. Thus, the PLCO trial will probably never be able to answer whether or not screening can influence prostate cancer mortality. In the ERSCP trial, the real benefit will only be evident after 10- 15 years of follow-up, especially because the 41% reduction of metastasis in the screening arm will have an impact.

Recent sub-analysis, with longer follow up have shown a potential benefit of screening, lowering the number of men needed to screen, and the number of patients needed to treat to safe one life.

Two key items remain open and empirical:


A baseline PSA determination at age 40 years has been suggested upon which the subsequent screening interval may then be based (5) (GR: B). A screening interval of 8 years might be enough in men with initial PSA levels < 1 ng/mL (6) . Further PSA testing is not necessary in men older than 75 years and a baseline PSA < 3 ng/mL because of their very low risk of dying from prostate cancer (7).

D'Amico in 1998 proposed a classification according to risk group for prostate cancer based on T stage, PSA value and Gleason. This has allowed to simplify the classification of patients with prostate cancer as well as trying to unify its treatment. (Table 1)

The widespread use of PSA testing has led to a significant migration in stage and grade of prostate cancer, with > 90% of men in the current era diagnosed with clinically localised disease (8). Despite the trends towards lower-risk prostate cancer, 20-35% of patients with newly diagnosed prostate cancer are still classified as high risk, based on either PSA > 20 ng/mL, Gleason score > 8, or an advanced clinical stage (9). Patients classified with high-

(PLCO) Cancer Screening Trial randomly assigned 76,693 men at 10 US centres to receive either annual screening with PSA and DRE or standard care as the control. After 7 years' follow-up, the incidence of prostate cancer per 10,000 person-years was 116 (2,820 cancers) in the screening group and 95 (2,322cancers) in the control group (rate ratio, 1.22) (3). The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screened group and 1.7 (44 deaths) in the control group (rate ratio, 1.13). The data at 10 years were 67% complete and consistent with these overall findings. The PLCO project team concluded that prostate cancer related mortality was very low and not significantly different between the two study groups. The European Randomized Study of Screening for Prostate Cancer (ERSPC) included a total of 162,243 men from seven countries aged between 55 and 69 years. The men were randomly assigned to a group offered PSA screening at an average of once every 4 years or to an unscreened control group. During a median follow-up of 9 years, the cumulative incidence of prostate cancer was 8.2% in the screened group and 4.8% in the control group (4). The rate ratio for death from prostate cancer was 0.80 in the screened group compared with the control group. The absolute risk difference was 0.71 deaths per 1,000 men. This means that 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer. The ERSPC investigators concluded that PSA-based screening reduced the rate of death from

prostate cancer by 20%, but was associated with a high risk of over-diagnosis.

arm will have an impact.

Two key items remain open and empirical: at what age should early detection start what is the interval for PSA and DRE.

low risk of dying from prostate cancer (7).

safe one life.

Both trials have received considerable attention and comments. In the PLCO trial, the rate of compliance in the screening arm was 85% for PSA testing and 86% for DRE. However, the rate of contamination in the control arm was as high as 40% in the first year and increased to 52% in the sixth year for PSA testing and ranged from 41% to 46% for DRE. Furthermore, biopsy compliance was only 40-52% versus 86% in the ERSPC. Thus, the PLCO trial will probably never be able to answer whether or not screening can influence prostate cancer mortality. In the ERSCP trial, the real benefit will only be evident after 10- 15 years of follow-up, especially because the 41% reduction of metastasis in the screening

Recent sub-analysis, with longer follow up have shown a potential benefit of screening, lowering the number of men needed to screen, and the number of patients needed to treat to

A baseline PSA determination at age 40 years has been suggested upon which the subsequent screening interval may then be based (5) (GR: B). A screening interval of 8 years might be enough in men with initial PSA levels < 1 ng/mL (6) . Further PSA testing is not necessary in men older than 75 years and a baseline PSA < 3 ng/mL because of their very

D'Amico in 1998 proposed a classification according to risk group for prostate cancer based on T stage, PSA value and Gleason. This has allowed to simplify the classification of patients

The widespread use of PSA testing has led to a significant migration in stage and grade of prostate cancer, with > 90% of men in the current era diagnosed with clinically localised disease (8). Despite the trends towards lower-risk prostate cancer, 20-35% of patients with newly diagnosed prostate cancer are still classified as high risk, based on either PSA > 20 ng/mL, Gleason score > 8, or an advanced clinical stage (9). Patients classified with high-

with prostate cancer as well as trying to unify its treatment. (Table 1)

risk prostate cancer are at an increased risk of PSA failure, the need for secondary therapy, metastatic progression and death from prostate cancer. Nevertheless, not all high-risk patients have a uniformly poor prognosis after RP (10). There is no consensus regarding the optimal treatment of men with high-risk prostate cancer. Decisions on whether to elect surgery as local therapy should be based on the best available clinical evidence.


Table 1. D'Amico classification of patients according to risk group

As expected, survival and success of the treatment applied in prostate cancer is closely linked to the stadium and the risk presented by the patient.

In this chapter we will focus on Prostate Cancer at high risk as well as the different therapeutic options, focusing on the radical prostatectomy as an effective treatment of the disease.
