Prostate cancer is one of the most frequent diseases in males, representing about 15% of all cancers diagnosed in men. Prostate cancer rarely occurs under the age of 45. The prostate is a gland found only in men that produces part of the seminal fluid released during ejaculation. Prostate cancer originates from the cells within the gland that begin to grow in an uncontrolled way.

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At the IEO prostate cancer is treated by a multidisciplinary team consisting of specialists in:

• Urogenital and Head and Neck Tumors Medical Treatment
• Urologic Surgery
• New Drugs and Early Drug Development for Innovative Therapies
• Department of Pathology and Laboratory Medicine
• Department of Medical Imaging and Radiation Sciences

To date, causes of prostate cancer are unknown, however some potential risk factors can be identified that could promote its onset.

• Age. Age is the main risk factor for this prostate cancer as it rarely occurs in men under the age of 45. Chances increase with age and, in our experience, the majority of men with prostate cancer are older than 60.
• Family history. For a man, the risk increases if his father or brother have a clinical history of prostate cancer.
• Race. Prostate cancer is more common in African American men compared to white people, including people of Hispanic origin. The frequency of prostate cancer is also lower in Asian men, and Native Americans.
• Diet. A few studies suggest that men following a diet rich in animal fat or meat may be more exposed to prostate cancer. Likewise men following a diet rich in fruit and vegetables appear to be at a lower risk of prostate cancer.
• Genetic and hormonal factors. Mutations of certain genes, such as BRCA1 and BRCA2 or HPC1, more frequently detected in subjects aged less than 55, as well as high levels of testosterone and IGF-1 may increase the risk of prostate cancer.

The incidence, that is the number of new cases of prostate cancer in a given period of time, is continually growing and has doubled in the last 10 years, due to the increase in the population’s average age and the introduction of the PSA (Prostate Specific Antigen) examination. Contrary to the increasing incidence of prostate cancer, mortality is constantly reducing, confirming the decisive role played by early diagnosis of prostate cancer through spontaneous screening based on PSA dosing and urological consultation.

Symptoms of prostate cancer

There is no specific primary prevention for prostate cancer even if there are a few behavioural rules that may be included in everyday life, such as increasing consumption of fruit, vegetables and whole grains, as well as reducing red meat and foods rich in unsaturated fats. It is good practice to maintain normal weight and keep fit by doing regular physical activity.

Before the development of prostate cancer symptoms, prostate cancer is currently diagnosed through spontaneous screening based on PSA evaluation and urological consultation.

Prostate cancer symptoms are not frequently detected until the cancer has grown large enough to put pressure on the urethra. This normally results in problems associated with urination.

Symptoms of prostate cancer can include:

• needing to urinate more frequently, often during the night
• needing to rush to the toilet
• difficulty in starting to pee (hesitancy)
• straining or taking a long time while urinating
• weak flow
• feeling that your bladder has not emptied fully

As men get older their prostate gland enlarges. It is not normally due to prostate cancer. It is a condition called benign prostatic hyperplasia (BPH). BPH doesn’t usually develop into prostate cancer. But an enlarged prostate might sometimes contain areas of cancer cells.

Diagnostic pattern for prostate cancer

The diagnostic pattern for prostate cancer includes:

• PSA, PCA3, PHI dosing (prostate health index)
• Digital rectal examination (urological consultation)
• Prostate biopsy

Staging can be completed by:

• Multiparametric magnetic resonance
• Abdominal and pelvis CT using contrast agent
• Bone scintigraphy

Nutritional prevention of prostate cancer

In addition, there are some nutritional recommendations prostate cancer. Based on a careful evaluation of the results from the scientific research, it has been possible to identify specific risk factors and protective nutritional factors for specific types of prostate cancer. Experts have classified the results into four levels: "convincing evidence", "probable evidence", "limited evidence" and one last level that collects the effects for which evidence of association with the tumour is “highly unlikely." Probable and convincing evidence forms the basis of the recommendations.

With regard to prostate cancer, a diet too rich in calcium is a probable risk factor. The consumption of lycopene-rich foods, such as tomatoes, pink grapefruit, watermelon, and foods rich in selenium, found mainly in fish, represent a probable protective factor for preventing the prostate cancer and avoiding symptoms of prostate cancer.

At the European Institute of Oncology, there is a specialised team for the diagnosis and treatment of prostate cancer, by considering the patient at the centre of the therapeutic process with an active role at each step.

Therapeutic approach to prostate cancer (surgery, radiotherapy and active surveillance)

Prostate cancer treatment has different goals depending on the extension and aggressiveness of the disease, the patient’s life expectancy and the presence of concomitant diseases that may represent a risk of death greater than that of the prostate cancer itself.

In order to select the appropriate treatment, the patient diagnosed with prostate cancer is evaluated by considering the prognostic factors related to cancer:

• clinical stage
• Gleason score biopsy
• PSA levels
• age
• comorbidities
• life expectancy.

Localised prostate cancer can be treated with surgery (prostatectomy is currently the most widely used treatment), radiotherapy, or active surveillance (in accordance with the criteria of the International PRIAS Programme). This approach involves the simple monitoring of the course of the prostate cancer evaluated by periodic repetition of PSA dosing and prostate biopsies, integrated at our centre by multiparametric MRI.

For patients eligible for radical treatment of prostate cancer with curative purposes, the European Institute of Oncology offers Robot-assisted surgery, that achieves great results in terms of prostate cancer eradication, a limited perioperative morbidity having little impact on patient quality of life, and an earlier recovery of functional outcomes compared to traditional surgery.

The use of prostate multiparametric MRI and the introduction of the PI-RADS assessment system, as published by ESUR, have proved to be of considerable support in setting up surgical planning, allowing for the identification of where the prostate cancer is most likely located and running intraoperative analysis, thereby favouring reduction of positive surgical margins.

Hormonal therapy of prostate cancer (including metastasized prostate cancer or locally-advanced cancers)

Testosterone produced by the male testes stimulates the growth of prostate cancer. Hormone therapy tries to counteract this action by slowing down or blocking testosterone synthesis (androgen deprivation).

Indications to hormonal therapy may be:

1. in metastatic or locally-advanced prostate cancers;
2. before and during radiotherapy especially in intermediate and high risk prostate cancer;
3. after curative surgery or radiotherapy, of prolonged or ultimate duration in high-risk patients in order to reduce the risk of prostate cancer recurrence.

Hormonal treatment can be carried out with different strategies:

• Surgical removal of both testicles (bilateral orchiectomy) allows us to achieve the best results in the shortest time, permanently reducing the circulating testosterone levels. Obviously, from a psychological point of view, this approach is difficult for the patient to accept, which is the reason that nowadays, unless the patient himself prefers this drastic solution for avoiding constantly receiving treatments, surgery is reserved for urgent cases, where it is necessary to quickly lower testosterone levels in order to reduce bone metastases compression on the spinal cord (spinal compression).
• Pharmacological therapywith different types of drugs that can reduce testosterone levels in the blood, such as:

- LHRH agonists (or GnRH) (gonadotropin-releasing hormone)

- LHRH antagonists (or GnRH) (gonadotropin-releasing hormone)

- Anti-androgens

Based on the patient and the prostate cancer characteristics, doctors may prescribe one of these drugs in isolation or in a combination of the two (for example LHRH agonists with anti-androgens to prevent the so-called "tumour flare"). The treatment for prostate cancer may be continuous or with short interruption periods (intermittent therapy), to reduce the impact of side-effects.

Analogs of LHRH agonists (or GnRH) and LHRH antagonists (or GnRH)

Testosterone secretion is regulated by the hypothalamus-pituitary axis, from which the cascade of messages pushing the testes (and ovaries) to produce sexual hormones starts. These drugs block the initial stimulus to the hypothalamus and have been shown to have the same effect as compared to surgical castration on testosterone circulating levels.

Anti-androgens

Testosterone stimulates the replication of prostate cancer cells by binding to specific receptors found on the surface of the cancer cells themselves. The anti-androgens are drugs that block the interaction between the male sexual hormone and these receptors, thereby inhibiting prostate cancer growth. They cause fewer erection disorders, but more pain in the breast compared with LHRH agonists. They can be associated with other drugs in the early stages of treatment for prostate cancer to reduce the effect produced by the increase - temporarily or for the entire treatment duration - in androgen production (cancer flare), in order to enhance their effect (total androgen blockage). In other cases, they can be used alone (either before or more often after the eventual intervention). The most common are: cyproterone acetate, bicalutamide, flutamide.

Therapy of castrate resistant prostate cancer

Prostate cancer may progress with increasing PSA, in the absence of remote disease or with the onset or progression of metastases during or after the classic hormone therapy. These cases are called castrate-resistant prostate cancer. In this phase, the prostate cancer is also able to grow and progress in the presence of low doses of circulating testosterone. Docetaxel and new agents such as Cabazitaxel, Abiraterone, Enzalutamide, Sipuleucel-T and Radium-223 have significantly changed the management of patients with metastatic castrate-resistant prostate cancer. All of these agents have demonstrated a significant survival benefit.

Responses to treatment for prostate cancer may vary depending on the associated comorbidities, extension and biological aggressiveness of the prostate cancer. The side-effects associated with treatment differ between drugs.

Treatment of metastasized prostate cancer, bone metastases and life expectancy

Bone metastases are the main driver of morbidity and mortality in metastasized prostate cancer. Targeting the bone microenvironment, a key player in the pathogenesis of bone metastasis, has become one of the mainstays of therapy in men with metastasized prostate cancer. Bone is a frequent site of metastases and typically indicates a short-term prognosis in cancer patients. Once cancer has spread to the bones it can rarely be cured, but often it can still be treated to slow its growth. The majority of skeletal metastases are due to breast and prostate cancer. Bone metastasis is actually much more common than primary bone cancers, especially in adults. The diagnosis of prostate cancer is based on signs, symptoms and imaging. New classes of drugs and new interventions are given a better quality of life to patients affected by prostate cancer and improved their life expectancy. A multidisciplinary approach is necessary to treat prostate cancer patients with bone metastasis. Bone metastasis are classified as osteolytic, osteoblastic or mixed, according to the primary mechanism of interference with normal bone remodeling. Bone metastases are a major cause for morbidity, characterized by severe pain, impaired mobility, pathologic fractures, spinal cord compression, bone marrow aplasia and hypercalcemia. Treatment decisions depend on several parameters, for example, if bone disease is localized or widespread, if there is evidence of extraskeletal metastases, the kind of cancer and its features, prior treatment history and disease response, the symptoms and the general state of health. Treatments can often shrink or slow the growth of bone metastases and can help with the symptoms they are causing but they are not curative. Bisphosphonates such as Zoledronic acid, which directly target osteoclasts, Denosumab, a receptor activator of nuclear factor‑kappa B (RANK) ligand inhibitor, which targets a key component of bone stromal interaction, and radium‑223, an alpha‑emitting calcium mimetic, which hones to the metabolically active areas of osteoblastic metastasis and induces double‑strand breaks in the DNA are considered specific treatment for metastasized prostate cancer and play a very important role in the management of prostate cancer symptom: they are able to control pain, and play an important role in the prevention of skeletal complications. Thus, pain management with analgesic and radiation should be utilized as indicated during the initiation of these therapies. Radiotherapy is the treatment of choice for localized bone pain, in presence of poorly localized bone pain or recurrence of pain in previously irradiated skeletal sites.