The word "prostate" comes from the Greek word "prostates," meaning "one who stands before." The prostate is a glandular organ found in males, located below the bladder and approximately the size of a walnut (about 20-25 grams). It produces various secretions essential for reproductive functions. As a man ages, it is normal for the prostate to enlarge, but if it becomes too large, it can obstruct the urethra (urinary canal) and make urination difficult. This enlargement is known as benign prostatic hyperplasia (BPH).

BPH is not cancer. In most cases, BPH is not a serious health concern and can be treated.

Introduction

Prostate cancer is a complex disease, and the characteristics of the disease, age, coexisting conditions, and personal preferences of patients will influence the choice of treatment. All available treatment options should be discussed with the patient.

Epidemiology and Risk Prevention

Prostate cancer is the second most commonly diagnosed cancer in men worldwide, with an estimated 1.1 million new cases in 2012. It is a significant health problem, particularly in developed countries where a large proportion of the population consists of elderly men. Unnecessary treatment following early detection is a potential risk for this disease. There are three well-known risk factors for prostate cancer:

• - Advanced age
• - Ethnicity
• - Genetic predisposition

Figure 1: Prostate anatomy and Prostate Digital Rectal Examination

The lifetime risk of developing prostate cancer is 15%, with a mortality risk of 2.9%. This disease is usually seen in men over the age of 65 and may not present any symptoms in its early stages. However, if left untreated, it can gradually enlarge and exert pressure on the urinary canal, leading to certain urinary complaints.

These symptoms may include;

1. • Difficulty or straining during urination
2. • Burning sensation during urination
3. • Intermittent urine flow
4. • Dribbling of urine after urination
5. • Decreased force of urine flow
6. • Presence of blood in semen or urine
7. • Pain during ejaculation
8. • Discomfort in the groin area
9. • Bone pain (in advanced stages with bone metastasis)
10. • Erectile dysfunction
11. • Paralysis (due to spinal metastasis)
12. • Bilateral obstruction of the urinary tract leading to kidney failure.

Regular prostate cancer screening for men is important for early detection because the earlier the disease is diagnosed, the higher the chances of successful treatment and survival. Screening involves measuring a biochemical parameter called PSA (Prostate-Specific Antigen) through a blood test and performing a digital rectal examination, which is a method of examining the prostate. In some cases where diagnosis and treatment are delayed, cancerous tissues can spread beyond the prostate to surrounding tissues.

Currently, there is no high-level evidence to suggest that preventive measures reduce the risk of prostate cancer.

Prostate Cancer Screening and Diagnostic Evaluation

Prostate cancer is usually suspected based on a digital rectal examination and/or elevated PSA levels. Definitive diagnosis is made by confirming cancer in prostate biopsy samples and surgical materials obtained for benign prostatic hyperplasia (BPH) evaluation. Considering the patient's age, comorbidities, and available treatment options, a decision should be made to perform advanced diagnostic and staging studies.

Any disruption in the prostate tissue can cause an elevation in PSA levels. These can include benign prostatic hyperplasia (prostate enlargement) other than cancer, prostatitis (prostate inflammation), sexual activity, biopsy, digital rectal examination, urinary tract infection, urinary interventions (catheterization), and surgeries.

Therefore, a high PSA level does not necessarily indicate cancer, and a low level may not be sufficient to rule out cancer. The treatment of prostate cancer is planned based on the tumor grade and stage.

For early detection, the approach in well-informed men with good performance status and a life expectancy of at least 10-15 years is as follows:

• • Men aged 50 and above
• • Men aged 45 and above with a family history of prostate cancer
• • African American men aged 45 and above

Early PSA screening is recommended.

Standard Prostate Biopsy and Tumor Grading

The most accurate way to determine if you have prostate cancer is through a prostate biopsy. A biopsy involves your doctor using a thin needle to take small tissue samples from your prostate. Therefore, a biopsy is only performed when other tests strongly suggest prostate cancer.

Biopsy samples are sent to a laboratory where a pathologist examines them under a microscope to check for cancer cells. The results will help your doctor plan and discuss treatment options with you

Pathologist: Pathologists are doctors who diagnose diseases by examining cells and tissue samples
There are two main types of prostate biopsies:
1. Transrectal ultrasound-guided biopsy or TRUS
2. Transperineal biopsy

It is important to discuss the risks and benefits of each procedure with your doctor to ensure it is right for you. Prostate biopsy is performed with "Transrectal Ultrasound-TRUS" imaging. A preparation process is planned before the prostate biopsy. The prostate is reached by inserting an ultrasound probe through the rectum. Local anesthesia is applied, and 12 tissue samples are taken from the prostate using a needle. After the tissues are obtained, they are sent for pathology examination. Biopsy procedures of this kind usually do not require any general anesthesia.

If the cause of elevated PSA levels cannot be determined, if PSA continues to rise, or if the biopsy results are suspicious, repeating the biopsy may be necessary.

Transperineal biopsy
During a transperineal biopsy, your doctor will insert a lubricated ultrasound probe into your rectum to visualize the prostate. The biopsy needle will then be passed through the skin between the testicles and the rectum. Transperineal biopsy is usually performed under local anesthesia, so the area will be numbed to minimize discomfort from the procedure. It is becoming more popular as it is believed to have a lower risk of serious infection

The most common grading system used is the Gleason Scoring System, which helps predict the behavior of prostate cancer. It provides us with important information about whether the disease is aggressive or indolent. The Gleason scoring system was first discovered by pathologist Dr. Donald F. Gleason in 1966. However, the system has undergone several changes since then. The current system used is the scoring system established by the International Society of Urological Pathology in 2014.

The Gleason Score, such as 3+4, 4+5, 3+3=6, 4+4=8, etc., summarizes the risk classification of prostate cancer. However, not only this score but also the TNM stage of the disease and the blood PSA level are important. Based on this:

• Gleason score ≤6 is considered low-risk prostate cancer.
• Gleason score = 7 is considered intermediate-risk prostate cancer.
• Gleason score 8-10 is considered high-risk prostate cancer.

d'amico prostate risk sınıflaması

D'Amico prostate risk classification: Prostate cancer staging: The spread of the tumor or its confinement within the prostate is taken into consideration.

1. • Tumor size
2. • Spread of the tumor within or beyond the tissues inside the prostate
3. • Involvement of lymph nodes
4. • Spread to other parts of the body (metastasis)

Stage 1

Prostate cancer is still confined to the prostate without detection of spread to surrounding tissues. PSA values during this stage are generally found to be below 10.

Stage 2

Prostate cancer is divided into two sub-stages: A and B. In stage 2A, cancer is still confined to one half of the prostate, while in stage 2B, cancer is detected in both halves of the prostate.

Stage 3

In the third stage, the tumor has spread beyond the prostate capsule and into tissues such as the seminal vesicles. There is no spread to lymph nodes or other parts of the body.

Stage 4

Prostate cancer has spread to the tissues surrounding the prostate. It can commonly metastasize to lymph nodes, bones, liver, or lungs.

Determining the grade of prostate cancer is crucial for appropriate treatment and monitoring the course of the disease.

Age

The incidence of prostate cancer increases with age. Only 2% of cases are diagnosed in individuals under 50 years old. The percentages of diagnosed patients in the age groups of <55, 55-64, 65-74, 75-84, and 85+ are approximately 9.7%, 30.7%, 35.3%, 19.9%, and 4.4%, respectively. The average age of death due to prostate cancer is 77. Autopsy studies have shown that the incidence of hidden prostate cancer is much higher than clinically detected cases. The rate of prostate cancer in autopsy studies ranges from 5% in men under 30 years old to up to 59% in the >79 age group.

Family History and Genetics:

YStudies have shown that about 15% of prostate cancer patients have a family history of prostate cancer among other family members. Certain gene groups have been identified to be responsible for the development of prostate cancer. Hereditary prostate cancer is defined as: a. Having 3 or more affected relatives. b. Having 2 or more relatives diagnosed with early-onset (before the age of 55) prostate cancer.

15.6% of men with prostate cancer have been found to have pathogenic variants in the tested genes (BRCA1, BRCA2, HOXB13, MLH1, MSH2, PMS2, MSH6, EPCAM, ATM, CHEK2, NBN, and TP53). Scientific studies have identified the most common disease-causing variants in BRCA2 (4.5%), CHEK2 (2.2%), ATM (1.8%), and BRCA1 (1.1%). The presence of Gleason 8 or higher is significantly associated with DNA repair pathogenic variants.

In addition, obesity and smoking are also among the recognized risk factors for prostate cancer.

DIET

It is known that maintaining a balanced diet and engaging in regular physical exercise keeps you healthy. A balanced diet includes consuming plenty of vegetables, fruits, and fiber, while limiting red meat, processed foods, high-fat foods, sugar, and alcohol. Overweight or obese men may increase their risk of developing prostate cancer

Epidemiological studies conducted particularly among individuals of Chinese and Japanese descent who migrated have shown the significant impact of diet and environmental conditions on the development of prostate cancer. However, more scientific research is needed in this area.

Inflammation and Infection

Inflammation and Infection Chronic inflammation has been shown to cause cancer in previous cases such as bladder, esophageal, gastric, and liver cancers. Scientific studies suggest a similar process may be involved in prostate cancer.

Additional tests can be performed to diagnose prostate cancer in individuals suspected of having the disease:

Multiparametric MRI

This imaging procedure, performed while the patient lies on a table, involves the use of a device with a cylindrical design. Contrast dye is injected intravenously, and the imaging process takes place over a variable duration of 30 to 45 minutes. Multiparametric MRI is a commonly used method as it significantly influences the treatment process. Patients do not experience any pain during the imaging session.

Multiparametric MRI is a diagnostic imaging method that can support the diagnosis of prostate cancer in patients with suspected disease. Compared to standard methods, MRI provides a high accuracy in determining the location and likelihood of cancer within the prostate, allowing for more precise guidance in treatment. The Prostate Imaging-Reporting and Data System (PI-RADS) classification system, developed in 2014, categorizes MRI images on a scale of 1 to 5 (with 5 indicating the highest suspicion of cancer). Multiparametric MRI provides the opportunity for more detailed examination and reporting of cancerous areas

PI-RADS 1 - Very low risk
PI-RADS 2 - Low risk
PI-RADS 3 - Intermediate risk (suspected for cancer)
PI-RADS 4 - High risk
PI-RADS 5 - Very high risk
Moreover, these MRI images can be used as a guide during prostate biopsy procedures.

MR-Ultrasound Fusion Biopsy

BIn this method, previously obtained multiparametric MRI images of the patient are transferred to an ultrasound device used for prostate biopsy, allowing for precise localization of the tumor. Instead of randomly sampling tissue as in conventional biopsies, this method enables targeted biopsies directly from suspicious focal points. By accurately locating the tumor or suspicious focus, fewer samples may be needed compared to taking numerous samples.

The fusion biopsy can be performed using two methods. One is the transperineal approach, which involves entering through the perineal region and can be done under general or local anesthesia. The other method is the transrectal approach, where entry is made through the rectum and can also be performed under local anesthesia.

Treatment Methods The treatment for prostate cancer is planned considering disease-related factors and patient-specific factors. The treatment plan is developed in collaboration with the patient.

Treatment for Localized Prostate Cancer:

• 1- Established Treatments:
  1.   • Radical Prostatectomy
  2.   • Radiation Therapy
• 2- Other Treatments::
  1.   • Active Surveillance
  2.   • Primary Hormonal Therapy
  3.   • Cryoablation
  4.   • Radiofrequency Ablation
  5.   • High-Intensity Focused Ultrasound (HIFU)

Which Treatment Method is commonly used for Prostate Cancer Cases? With the increasing use of prostate cancer screening tests, it can be detected in the early stages. For localized prostate cancer that has not spread to the surrounding tissues, surgical treatment is the most commonly used approach. It can be combined with hormone therapy or radiation therapy if necessary.

Active Surveillance It involves deferring primary treatment until biochemical and histological signs indicating disease progression appear.

Patients who may be eligible for active surveillance:
• Clinical stage T1-2a
• PSA less than 10 ng/mL
• Biopsy with Gleason score ≤6, involving 2 or fewer cores
• Involvement of less than 50% of any core

During active surveillance, patients should be evaluated every 3-6 months with a digital rectal exam (DRE) and PSA test, and undergo a prostate biopsy every 1-2 years. This helps prevent unnecessary treatment in a group of patients.

Watchful Waiting Also known as deferred or symptomatic treatment. It involves monitoring the patient until local or systemic progression-related symptoms occur. It can be applied in cases where life expectancy is short, in elderly patients, or in tumors with slow progression.

Surgical Treatment for Prostate Cancer

Radical Prostatectomy Radical prostatectomy is the primary treatment method for localized prostate cancer that has not spread beyond the prostate gland. It has been in use for over 100 years. Radical prostatectomy involves the complete removal of the prostate gland through surgery for the treatment of prostate cancer. During the procedure, the adjacent seminal vesicles and the tips of the seminal ducts are also removed. In some cases, the lymph nodes in the pelvic region may also need to be removed, which is called lymphadenectomy. The prostate is located just below the bladder and the urethra passes through it. After the prostate is surgically removed, the mouth of the bladder and the urethra are stitched together to create a connection that allows urine flow.

Due to the increased risk of death from causes other than prostate cancer with advancing age, radical prostatectomy should be performed in patients with a life expectancy of over 10 years.

Robot Assisted Radical Prostate Surgery;

The goal of radical prostatectomy is to completely remove the cancer, prevent urinary incontinence in the postoperative period, and preserve erectile function as much as possible. In this regard, robotic-assisted radical prostatectomy demonstrates superior outcomes compared to other surgical methods. The advantages of robotic surgery include a larger visual field, the ability of robotic arms to reach areas that human hands cannot access, and a less bloody surgical field. Therefore, robotic surgery yields better results in terms of cancer control compared to open and laparoscopic surgery. The recovery period for achieving urinary control is faster in robotic surgery compared to laparoscopic and open surgery. Due to better preservation of the nerves located on both sides of the prostate in robotic-assisted prostate surgery, sexual dysfunction and erectile problems are relatively less frequent compared to other surgical methods.

Complications of Robot-Assisted Prostate Cancer Surgery

Complications of Robot-Assisted Prostate Cancer Surgery: The anatomical location of the prostate tissue, which is responsible for maintaining erections and urinary continence, is in close proximity to the vascular nerve bundle. Possible complications of robotic surgery for prostate cancer include:
1. Urinary incontinence: Difficulty controlling urine flow or experiencing leakage after surgery.
2. Erectile dysfunction: Loss of ability to achieve or maintain an erection.
3. Difficulty urinating: Problems with initiating or maintaining urine flow.
4. Infection: Risk of developing infections in the surgical area.
5. Bleeding: Possibility of bleeding during or after the surgery.
6. Bowel problems: Rarely, bowel-related complications such as injury or obstruction may occur.
7. Scarring: Formation of scar tissue in the surgical area.
8. Deep vein thrombosis: Blood clot formation in deep veins, usually in the legs.
9. Pneumonia: Inflammation and infection of the lungs, which can occur post-surgery due to decreased mobility.
10. Hernia: Occasional development of a hernia at the incision site.

Robot-Assisted Surgery:

Is the Robot Performing the Surgery? There is a common misconception in the community about whether the surgery is performed by the surgeon or the robot. Robot-assisted surgery is performed with the assistance of a robotic system called Da Vinci. The robot is carefully positioned over the patient, and the surgeon controls its robotic arms from a console unit called the console. The principles of robot-assisted surgery are similar to laparoscopic surgery. The surgical instruments used during the procedure have a high level of functionality. Attached to the robot's arms, these instruments can mimic the movements of the human wrist and fingers while providing a wider range of motion and vibration-free operation. This minimizes the risk of complications, reduces blood loss, and shortens the duration of the surgery. Open prostate surgeries often have longer recovery times, extended hospital stays, higher risk of wound infection, and leave larger scars. Limitations in hand movements and restricted visibility due to the narrow surgical field contribute to longer surgery times and increased complication rates. Following robot-assisted prostate surgery, patients experience reduced pain, shorter recovery times, and decreased health problems that significantly impact their social lives, such as loss of sexual function and continuous urinary incontinence.

Radiation Therapy Radiation therapy is the treatment of a disease using radiation. It is usually performed by delivering radiation beams, typically photons, directly to the prostate and surrounding tissues from various angles. To minimize radiation damage to the bladder and rectum, a computer-based technique called 3D-conformal radiation therapy (3D-CRT) has been developed, which focuses the radiation beams onto the prostate. Intensity-modulated radiation therapy (IMRT), which is an advanced form of 3D-CRT, can deliver sufficient radiation to hard-to-reach areas geometrically.

Radiation therapy is a local treatment method similar to surgery; it demonstrates its effects and side effects at the site where it is applied. In localized prostate cancer, radiation therapy can be used as a curative treatment method, and in cases where the cancer has spread to neighboring organs (locally advanced) or distant organs (metastatic), it can be used as a palliative treatment (aimed at relieving symptoms) or for reducing tumor burden.

What are the Side Effects of Radiation Therapy? The side effects of radiation therapy typically begin to occur in the later days as the dose increases, rather than in the initial days. Some common side effects include skin irritation and a feeling of fatigue. Radiation therapy used for prostate cancer can cause erectile dysfunction and urinary incontinence. Additionally, frequent urination and blood in the urine may occur in some cases.

Chemohormonal Therapy In advanced stages of prostate cancer, the disease may be detected as spreading to neighboring tissues and distant organs, rather than being confined to the prostate alone. In such stages where surgical methods are inadequate, drug treatments are preferred. Since prostate tissue is sensitive to the male hormone testosterone, drugs (anti-androgens) that block the effects of testosterone are used in this treatment. This treatment is called hormone therapy.

For patients who do not respond or develop resistance to this treatment, chemotherapy is planned. Scientific studies have shown that through chemotherapy, the survival of patients with advanced-stage prostate cancer can be prolonged.

High-Intensity Focused Ultrasound (HIFU) The working mechanism of HIFU involves generating heat based on the relationship between ultrasound waves and tissue, high pressure, cavitation bubbles, and eventually the formation of necrosis (cell death) along with the production of free chemical radicals that wash out the tissue. This process may take days or even months if necessary. HIFU energy can be repeated. The treatment is performed under general or spinal anesthesia and typically takes between 1 to 4 hours, depending on the volume of the prostate.

In this treatment, the prostate volume should not exceed 40cc. Most patients require urethral catheterization or suprapubic catheterization for a few days. HIFU is generally well-tolerated. The most common side effect is sudden urinary retention (20%). Other side effects include erectile dysfunction, incontinence, urethral stricture, and pain.

Cryotherapy Cryotherapy involves inserting thin needles into the prostate through the skin between the testicles and rectum. Once inserted, it freezes the tumor(s) to destroy the cancer cells inside. It is usually administered to men with early-stage prostate cancer.

If you have multiple tumors or if it is given to a small area of the prostate, the treatment can be delivered to the entire prostate. Both methods are performed under general or spinal anesthesia.

During the procedure, an ultrasound probe is gently inserted into the rectum. The probe produces ultrasound images of the prostate to help your doctor see the tumors more clearly and ensure that the needles are placed correctly.

Cryotherapy is a specialized technique and may not be available in all hospitals. In some countries, cryotherapy may be available as part of a clinical research study.