Prostate cancer

Prostate cancer is defined as cancer that develops in one of the glandular organs of the male reproductive system called the prostate. Cancer occurs when some prostate cells mutate and begin to multiply uncontrollably. These could also spread from the prostate to other parts of the body, especially the bones and lymph nodes, causing metastasis. This condition can cause pain, difficult urination, erectile dysfunction, among other symptoms.

The disease most often develops in individuals older than 50 years. It is the second most common type of cancer in men. However, many men who develop prostate cancer never have symptoms or undergo therapy. Various factors, including genetics and diet, have been implicated in its development, but to date (2005), known primary prevention modalities are insufficient to eliminate the risk of contracting the disease.

269 genetic risk variants have been identified, generally associated equally with the risk of aggressive disease and non-aggressive disease (it does not differentiate the risk of aggressive vs. non-aggressive prostate cancer). Alterations or mutations have been found in the genes AR, MYC, PTEN and BRCA2. The androgen receptor (AR) gene is associated with the androgen insensitivity. MYC is a proto-oncogene and encodes a nuclear phosphoprotein that plays a role in cell cycle progression, apoptosis, and cell transformation. PTEN is a multifunctional tumor suppressor that is frequently lost when cancer is present. BRCA2 has been related to the susceptibility to developing different types of cancer, including prostate cancer.

Prostate cancer can originate in luminal cells or cells of neuroendocrine origin. 95% of cancers originate from luminal secretory cells, while only 1-5% have a neuroendocrine origin. Luminal cells are characterized by expressing androgen receptors while basal cells have very low levels or do not express androgens.

Detection is carried out mainly by the blood test for prostate-specific antigen, called PSA (English acronym for prostate-specific antigen) or by physical examination of the prostate gland (rectal examination). Suspicious results typically result in the subsequent removal of a tissue sample from the prostate (biopsy), which is examined under a microscope.

Treatment may include surgery, radiation therapy, chemotherapy, or a combination of all of these. The age and general health of the affected person, as well as the extent of the spread, the appearance of the tissues examined microscopically, and the response of the cancer to the initial treatment, are vital in determining the therapeutic result.

Pathology and natural history

Histology

Although the prostate is made up of many different types of cells, more than 99% of prostate cancers develop on cells of a gland. The glandular cells produce the seminal fluid that is secreted by the prostate. The medical term for cancer that originates in glandular cells is called adenocarcinoma. Because the other types of prostate cancer are very rare, when you talk about prostate cancer, you most likely mean adenocarcinoma. It is rare to find sarcomas, transitional cell carcinoma, small cells, epidermoid or squamous. The prostate can be the seat of metastases, bladder cancer, colon cancer, lung cancer, melanoma, lymphoma, or other neoplasms.

Growth

Most prostate cancers grow very slowly and persist for a long time without causing major symptoms. Studies of autopsy series show that the majority of older men who die from other diseases also have prostate cancer that no one has ever diagnosed before. Only about a third of the cases discovered at necropsy have manifested clinically. It is equally unknown whether the tumors can become more malignant over time.

Prostatic Intraepithelial Neoplasia

Some doctors believe that prostate cancer comes from a lesion called prostatic intraepithelial neoplasia (PIN). PIN begins to appear in men from the age of 20. Nearly 50% of men who have PINs reach age 50. In this situation there are changes of microscopic appearance (size, surface, etc.) of the cells of the prostate gland. These changes are classified as low-grade, meaning they look quite similar to normal cells, or high-grade, meaning they are highly altered cells and different from normal cells. If a high-grade PIN is diagnosed by biopsy, there is a 30-50% chance of also having prostate cancer. For this reason, men diagnosed with a high-grade PIN are closely followed with periodic prostate biopsies.

Location

Prostate cancer tends to be multifocal and often involves the glandular capsule. Unlike benign prostatic hyperplasia (BPH), prostate cancer predominates in the periphery of the prostate. Both characteristics (multifocal and peripheral) make transurethral resection (TUR) not a form of curative therapy.

Prevention

Primary prevention

Current information on risk factors for prostate cancer suggests that some cases can be prevented. A possible risk factor that can be changed is diet, with a relationship, for example, between the consumption of polyphenols in red wine and a lower incidence of this type of cancer. It is possible to reduce the risk of suffering from this cancer by consuming a low diet. fat and rich in vegetables, fruits and cereals.

It appears that vitamin and mineral supplements may lower the risk of developing it. The mineral selenium can also reduce the risk. In any case, vitamin supplements must be consumed with caution. A richly varied diet with a predominance of foods of vegetable rather than animal origin, which contain all these micronutrients and which act positively and synergistically, is more recommendable.

According to T. Colin Campbell, in The China Study, dairy consumption is related to prostate cancer. Research conducted at Harvard in concluded that twelve out of fourteen case-control studies and seven of nine cohort studies demonstrated a positive association between a given amount of dairy and prostate cancer. According to the results, this is one of the most concordant nutritional indicators for prostate cancer "in all published scientific literature". In these studies, men who ate the most dairy products had approximately twice the risk of prostate cancer and four times the risk of metastatic or fatal prostate cancer, compared with those who ate the least amount. of said foods.

The Prostate cancer prevention trial is a clinical trial, which has recruited more than 18,000 men over the age of 50, to determine the protective effect of a substance called finasteride, capable of protecting the prostate from the masculine hormones, being able to reduce the risk of cancer. Despite the expectations created, the use of finasteride was associated with a higher frequency of adverse effects of a sexual nature. In addition, it was observed that the group treated with the drug showed a higher rate of more aggressive prostate cancers,^{[citation needed]} a scientifically plausible effect.^{[citation needed]} Finally, it should be noted that the prevalence of prostate cancer among those who took a placebo was much higher than expected, thus raising doubts about the results and applicability of said study.

It appears that nonsteroidal anti-inflammatory drugs, such as aspirin and ibuprofen, taken daily are associated with a lower incidence of prostate cancer in men age 60 and older, according to some studies.

Early detection

It can often be detected early with a prostate-specific antigen (PSA) blood test. Prostate cancer can also be detected early when a digital rectal examination is performed. Because the prostate gland is located just in front of the rectum, digital rectal examination can tell if there are nodules or hard (woody) areas in the prostate, often indicating cancer. If these tests are routinely performed annually and any of the results are abnormal, we have a chance of diagnosing cancer in an early stage.

The American Cancer Society believes that health professionals should offer blood tests for prostate-specific antigen, commonly called PSA (prostate-specific antigen) and digital rectal exams annually starting at age 50, to males who have a life expectancy greater than 10 years. High-risk men, such as African-Americans and men with first-degree relatives (father, brothers, uncles) diagnosed with prostate cancer at an early age, should be tested starting at age 45.

Although genetic risk scoring (GRS) systems do not predict who is more likely to develop aggressive disease (versus non-aggressive disease), they can define a subset of men in whom a substantial fraction of cases will develop aggressive: 45 to 51% of all men with aggressive prostate cancer in these populations have a GRS in the top 20%. Currently, genetic information is not incorporated into the decision-making process for screening with the prostate-specific antigen (PSA) test. However, men with high GRS may benefit from earlier and more frequent screening, while knowledge of low GRS may help reduce unnecessary biopsies for men with borderline PSA levels at screening.

Health care professionals should facilitate an open discussion with their male patients about the benefits and risks of annual testing. Patients should actively participate in this decision to learn about prostate cancer and the pros and cons of early detection and treatment.

The Prostate, Lung, Colorectal and Ovarian Cancer Screening Study, funded by the US National Cancer Institute, is designed to show whether certain screening tests can reduce the number of deaths from these cancers. cancers. This study is evaluating the usefulness of early detection with digital rectal examination and blood PSA level in men aged 55 to 74 years. The results will be available from 2010, when the study ends.

Prostate Cancer Antigen-2

Prostate Cancer Antigen-2 or APCP-2 is the most recent discovery made at Johns Hopkins University in Baltimore. It is a protein that is present in 90% of the cases studied where prostate cancer was confirmed and in 98% of the cases where it had spread beyond it, leaving a relative level of false negatives in comparison with the Prostate Antigen test. On the other hand, it has a low false positive rate, since it has a 97% accuracy rate when it comes to verifying that a patient does not suffer from prostate cancer. These findings were published in the May issue of Urology.

Prostate Specific Antigen (PSA)

Prostate-specific antigen (PSA) is a protein substance synthesized by the normal prostate and whose function is to dissolve the seminal clot. Its production depends on the presence of androgens and the size of the prostate gland. It is practically an exclusive protein synthesis in the prostate. A very small part of this PSA passes into the blood circulation and it is precisely this PSA that passes into the blood that is measured for the diagnosis, prognosis and follow-up of prostate cancer. PSA blood levels in healthy men are very low, in the order of millions of times less than semen, and are elevated in prostate disease. The reference values for the serum PSA vary according to the different laboratories, although these are normally situated at 4 ng/mL. The cut-off point for normal levels also increases with the age of the patient. In this way, serum PSA levels of 4 ng/mL can be considered high in a 50-year-old person and normal in an 80-year-old. PSA levels fluctuate randomly in the order of 15% in the same individual. Thus, a PSA test of 3 ng/mL can be repeated on another occasion and could give a result of 3.2 or 2.8 ng/mL naturally. In a hospitalized patient, levels can drop by as much as 50%. Although PSA is most abundant in semen, a small proportion is also found in the blood. Most men have PSA levels below 4 nanograms per milliliter of blood. The serum PSA level is the most sensitive test for early detection of prostate cancer, since it rises in approximately 65% of cases.

Dreal examination

Although digital rectal examination is less effective than the PSA blood test, to detect prostate cancer at an early stage it is essential that it be performed as part of the physical examination, because nodules, indurations, irregularities, or asymmetries can sometimes be palpated in patients who have normal PSA levels and who would require a biopsy to rule out or confirm the presence of prostate cancer. For this reason, the guidelines of the American Cancer Society recommend the joint use of both the digital rectal examination and the PSA blood test for early detection. Digital rectal examination is also used when it is known that one has prostate cancer, to classify the state of the disease and to determine, clinically, if the cancer has exceeded the limits of the prostate gland or to detect recurrences after treatment.

Transrectal ultrasound of the prostate

It should be performed when the digital rectal examination is positive or when the PSA is elevated. And be ordered together with the transrectal prostate biopsy. This procedure is carried out on an outpatient basis. Currently it is performed under anesthesia (sedation) and requires prior preparation (antibiotics and enemas). Transrectal ultrasound is the most widely used method to guide the needle that will extract the tissue sample for prostate biopsy. Prostate tumors and normal prostate tissue occasionally reflect different sound waves; tumors, when detected ultrasonographically, appear as hypoechoic images usually located on the periphery of the gland. However, most prostate tumors are isoechoic, thus indistinguishable from normal prostatitis tissue. For this reason, transrectal ultrasound of the prostate is used to guide the biopsy needle and take multiple samples, in different areas of the prostate gland, which is known as prostate mapping, and additionally perform a biopsy of the lesion or nodule that is detected during ultrasound study of the prostate. Transrectal ultrasound, by itself, is an insensitive and non-specific technique for use as a screening test, so transrectal ultrasound is not routinely recommended as an early detection test.

Diagnosis

If some symptoms or early detection test results raise the possibility of prostate cancer, further testing is required to decide if the disease is present.

Signs and symptoms

Early prostate cancer usually causes no symptoms and is detected by a PSA elevation or by performing a digital rectal examination. The presence of symptoms is indicative that it is in an advanced phase. Symptoms include: dysuria, urgency, frequency and nocturia, urinary retention, dribbling, and terminal hematuria. The sudden onset and rapid progression of urinary obstructive symptoms in men of the appropriate age group is highly likely to be caused by prostate cancer.

Staging

The stage or stage of a cancer is the most important factor in choosing the most appropriate treatment option and predicting the patient's prognosis. If cancer is confirmed, more diagnostic tests are needed to find out the extent of cancer within the prostate and outside of it (in the vicinity of the prostate or in other parts of the body: distant, disseminated, or metastatic disease). This process, called staging, provides information about the cancer with various tests to determine the extent of the cancer.

The data obtained from digital rectal examination, PSA level and Gleason score allow us to know what tests are needed for the extension study. Men with a normal DRE, low PSA, and low Gleason score most of the time do not need any further tests, because the chance that the cancer has spread outside the prostate is very low.

Physical examination

The physical examination, especially digital rectal examination, is an important part of prostate cancer staging. With DRE data, you can sometimes tell if the cancer is only on one "lobe" of the prostate, if it is present on both sides and if it has a high probability of spreading outside the prostate gland. It should be explored if the prostatic sulci are present or obliterated and if the seminal vesicles are palpable or not (they are normally not palpable). Inguinal lymph nodes should also be palpated for metastatic lymph nodes (rare). Digital rectal examination is always used together with the PSA blood test for the early detection of prostate cancer.

Images

MRI for the detection of prostate cancer

Starting in 2011, MRI was used to identify targets for prostate biopsy using fusion MRI with ultrasound or MRI guidance alone. An MRI alone will correctly identify 91% of men with clinically significant prostate cancer, but will misclassify 63% of men at risk for prostate cancer as having clinically significant cancer. An MRI-directed biopsy will correctly identify to 80% of patients with prostate cancer. However, it will classify the 6% of men at risk for cancer as having clinically significant cancer.

After an MRI, regions of interest within the scan that may be cancerous are often rated on a probability scale between 1 and 5. One of those scales is the Imaging Reporting and Data System. (PI-RADS) which defines clinical service standards for multiparameter magnetic resonance imaging (mpMRI), including image creation and reporting. The PI-RADS version 2 score has shown a specificity and sensitivity of 73% and 95%, respectively, for the detection of prostate cancer.

When an MRI is used to decide whether to have a biopsy in men who have had a previous biopsy, it is 5% more likely to make a correct diagnosis than a standard biopsy and 12% more likely to be correct for men who may or may not have had a prior biopsy. In men who had a negative biopsy, this combination is 44% more likely to lead to a correct diagnosis.

Treatment

The treatment of prostate cancer is governed by the available scientific information that is adapted to the health system and economic resources of each region or country. It must be individualized and consider many factors, especially:

• Age and life expectancy.
• Patient preferences for side effects associated with each treatment.
• Any serious illness the patient suffers.
• The state and degree of cancer.
• The probability of each type of treatment being curative.

With the PSA data, Gleason score and clinical stage T (Partin Tables), the probability that prostate cancer is:

• Confine organ disease.
• Extraprostatic extension (capsular rotation).
• Seminal vesicles invasion.
• Invasion of pelvic lymph nodes.

It is a widespread custom in the United States (and it is becoming increasingly important in Spain) for the patient to request a second opinion about the best treatment option, depending on their situation, especially if there are several options available. The patient must weigh, together with his urologist and her family, the benefits of each of the treatments and also the possible side effects and risks.

Expectant Management

If the cancer does not cause any symptoms, grows very slowly, and is very small, confined to a small area of the prostate, watchful waiting is recommended. In certain circumstances this may be the best option. This type of treatment is generally reserved for men over 80 years of age. Because prostate cancer often grows very slowly, if the patient is older or has other serious illnesses, treatment is not necessary. Some men choose to wait and see, because they don't want to suffer the side effects of aggressive treatments.

Maintaining expectant management does not mean that the patient will not receive any medical care or follow-up. On the contrary, the cancer will be observed and monitored. Blood PSA determinations and digital rectal examination are usually performed every 6 months, possibly with transrectal ultrasound-guided biopsy annually. If the patient develops any symptoms or the cancer grows more rapidly, consideration should be given to moving on to active treatment.

A large study sponsored by the National Cancer Institute and the Veterans affairs cooperative studies program is currently underway to clarify how active treatment affects survival and quality of life. of life of patients with prostate cancer at different ages, called PIVOT (English acronym for Prostatic Intervention Versus Observation Trial).

Surgery

Radical prostatectomy is surgery performed with the intent to cure prostate cancer. Traditionally, surgery has been performed on men under 70 years of age. It is most often done when the cancer has not spread beyond the prostate gland (stages T1 or T2). In this operation, the urologist tries to cure the cancer by removing the prostate gland. To do this, surgeons used to make an incision in the lower abdomen to take out the prostate, a procedure called open radical prostatectomy (ORP). Surgeons recently began to use laparoscopic radical prostatectomy (LRP), which is performed by suprapubic laparotomy, which is currently the reference technique or gold standard because it is a less invasive surgery and with similar results. A variant is robotic radical prostatectomy, with the use of the Da Vinci robot, which achieves similar results with fewer transfusion requirements.

Radiation therapy

Radiation therapy uses high-energy (megavoltage) x-rays or particles to kill cancer cells. Radiation treats low-grade cancer that is confined to the prostate or has only invaded neighboring tissue. Radiotherapy cure rates are similar to those obtained with radical prostatectomy. If the disease is more advanced, radiation may be used to shrink the tumor and provide relief of current or future symptoms. Traditionally, radiation therapy has been reserved as first-line treatment in men between 70 and 80 years of age with prostate cancer and other health problems that contraindicate surgery.

Low Rate Brachytherapy

Low dose rate brachytherapy is a minimally invasive treatment that consists of implanting tiny radioactive sources (seeds), generally Palladium or I-125, directly into the prostate. With results equal to or better than radical surgery and external radiotherapy in the treatment of low-risk localized prostate cancer, it has lower morbidity and better patient quality of life, as confirmed by the studies of the Prostate Cancer Results Study. Group (PCRSG) and the Prostate Cancer Center of Seattle.

Cryosurgery

Cryosurgery, also called cryotherapy or cryoablation, is sometimes used to treat localized prostate cancer by freezing the tumor cells with a metal cryoprobe.

Warm salt water is circulated through a bladder catheter to protect it from freezing. The metal probe is inserted into the prostate through a small incision in the skin of the perineum guided by transrectal ultrasound. Epidural or general anesthesia is required during this procedure. In Spain there are still few highly specialized centers where cryotherapy is practiced.

High Intensity Focused Ultrasound (HIFU)

One of the many applications of HIFU technology is to treat localized prostate cancer using high-intensity focused ultrasound ("HIFU"). The energy is released from an endorectal probe. The ultrasound waves travel through the walls of the rectum without damaging it and are focused on the prostate. This focusing produces intense and instantaneous heating that causes the irreversible destruction of the selected area, without damaging the surrounding tissues. The treatment, which lasts from 1 to 3 hours, can be carried out under epidural anesthesia. This therapeutic option is currently no longer considered experimental.

Androgen Hormone Blockade

The goal of hormone treatment is to lower levels of the male hormones, androgens. The main androgen is called testosterone. Androgens, produced primarily in the testicles, promote the growth of prostate cancer cells. When androgen levels are low, prostate cancers shrink and grow more slowly. But hormone treatment does not cure cancer nor is it a substitute for curative treatment.

Hormone treatment can be used in several situations:

• As a first line (initial or primary treatment) if the patient is not prepared for surgery or radiation therapy or cannot be cured with these treatments because the cancer has exceeded the limits of the prostate.
• After initial treatment, such as surgery or radiation therapy, if the cancer persists or has relapsed.
• Along with radiation therapy as initial therapy (adjuvant therapy) in certain groups of men who have a high risk of recurrence.
• Some doctors are testing hormonal treatment before surgery or radiation therapy (neoadjuvant treatment), with the aim of reducing cancer and making primary treatment more effective. The effectiveness of this procedure is not yet demonstrated, but it seems to be superior with radiation therapy.
• Some doctors think that hormonal block treatment is more effective if it starts as soon as possible, once the cancer has been diagnosed in an advanced stage, but not all doctors agree.
• Traditionally, the complete androgenic block has been reserved for males over 80 years of age with symptomatic or advanced prostate cancer.

In addition, when prostate cancer is metastatic and becomes resistant to hormonal treatment due to the acquisition of mutations during it by therapy directed at the androgen receptor, the need arises to develop new therapies directed at the signaling of this receptor. Agents emerging from standard care and investigation, such as 177Lu-PSMA617, degraders of the androgen receptor protein, and inhibitors of the N-terminal domain of this receptor, offer renewed strategies to exploit the dependence of AR signaling. It is also essential that drugs be administered on a continuous androgen deprivation basis.

Chemotherapy

Chemotherapy is sometimes used if prostate cancer has spread outside the prostate gland and hormone treatment is not working (hormone resistance). In “systemic chemotherapy” drugs are given intravenously or orally, which enter the bloodstream and reach all parts of the body, making this treatment potentially effective in cancers that have metastasized (spread to organs distant from the prostate).

The goal of this treatment is not to kill all the cancer cells, but it can slow the growth of the cancer and reduce pain. Objective partial response is obtained between 10 and 40% of cases. Chemotherapy is not indicated as treatment in case of early prostate cancer.

Palliative treatment

Most of the above treatments are aimed at killing or destroying prostate cancer cells, or slowing their growth. It is also a very important objective to take care of the "quality of life" of the patient, trying to eliminate, or reduce, the pain and other symptoms that afflict the patient. Some very effective methods to achieve this are:

• With painkillers, especially opioids.
• With biphosphonates, substances that can relieve pain caused by bone metastases and also slow the growth of these metastases. Zoledronic acid (Zometa) is the first recently approved biphosphonate for the use of bone metastases of prostate cancer.
• With steroids such as prednisone and dexamethasone, they can relieve bone pain in some men with metastatic prostate cancer.
• With radiation therapy. Both external and radiopharmaceutical radiation therapy can calm bone pain.

Some studies have shown that patients who receive good analgesic treatment feel better, live longer, and can perform their activities more normally.

Options according to stage

The stage of the prostate cancer is one of the most important factors in deciding the most suitable treatment. Treatment options are based on the AJCC (TNM) system:

• Stadium I: If the patient does not present any symptoms, it is greater or has some important health problem, keeping an expectant behavior may be the best option. If the patient is young and has good health, radical prostatectomy or radiation therapy should be considered, especially if the Gleason or PSA score is not very low.
• Stadium II: Because of its tendency to increase growth and symptoms, it is usually offered (according to age and state of health): prostatectomy, radiation therapy, brachytherapy or combined therapy.
• Stage III: An expectant behavior can be taken for older men in which cancer does not produce symptoms or have significant health problems, keeping stage II options, adding androgenic suppression therapy alone or in combination with other treatments.
• Stage IV: At this stage are the following palliative options: treatment of androgenic suppression, radiation therapy, transuretral resection (paliative) and other treatments to decrease symptoms caused by metastasis. Biphosphonates may be used for bone metastases and chemotherapy may be offered in selected cases.

Metastasis and genetic alterations

Prostate cancer due to dependence on pathways regulated by androgen receptors has high progression and metastasis in the bone as well as at the lymph node level. Genomic studies in metastatic prostate cancer have identified alterations in signaling pathways and different altered genes such as AR, TP53, RB1, PTEN among others. Loss of PTEN together with transcriptional deregulation of MYC may synergize to induce genomic instability and aggressive prostate cancer. In one study they used a genetically engineered mouse model with PTEN/TP53 deficiency and showed that deletion of PTEN and TP53 activated metastasis and these lesions showed activation of MYC in the absence of AKT activation. There are several genes involved in the process of prostate carcinogenesis in such a way that it is essential to study the signaling pathways involved in the process. development of said tumor. Another gene that is frequently altered is RB1, which is involved in the regulation of the cell cycle and in the transcriptional regulation of mitotic checkpoint genes. Loss of function of RB1 triggers dysregulation of the expression of hypoxia-mediated transcriptional processes characterized by angiogenesis and metastasis. In a mouse model, deleting RB1 facilitated metastasis of prostatic adenocarcinoma initiated by the PTEN mutation, and further loss of TP53.

Metastatic prostate cancer triggers bone problems that must be characterized pathologically and at the molecular level through bone biopsies. However, obtaining bone biopsies is cumbersome and difficult to perform, and in most cases very small amounts are obtained that are not suitable for molecular analysis. At present, it has revolutionized the way of molecular and genomic analysis, opting for liquid biopsies, that is, blood tests from patients with prostate cancer that help to investigate the heterogeneity and clonal evolution over time of a therapy. Specifically, samples of circulating tumor DNA are taken from patients and mutations are analyzed by whole genome sequencing (Whole genome sequencing). It is a minimally invasive technique that detects genomic resistance mechanisms.