The importance of the early diagnosis of the prostate cancer

The early diagnosis of PCa has been facilitated by the determination of the prostate specific antigen (PSA), rectal touch and ultrasonography, which has subsequently led to a high cure rate in the early stages (stage I/II) of the disease. However, it is important to have in mind, that these current diagnostic techniques have not, in several cases, sufficient specificity and sensitivity to determine the stage and aggressiveness of the PCa and to identify appropriate treatment [2, 6, 35-37].

International guidelines support opportunistic PSA screening in well-informed patients and recommend a baseline PSA at 40 years of age. Although some relevant controversies continue about the real benefit of the screening program, the undisputable finding is that an increasing percentage of young men have an early PCa diagnosis and this condition has the advantage to permit curative interventions [2, 35-37].

When a man has the PCa early diagnosed, he has a number of treatment options, which carry similar success rates. Surgery, brachytherapy or external beam radiotherapy in combination with several months of initial hormone treatment all carry the same chance of cure but they all have very different recovery times, or number of visits to the hospital to consider [4, 6].

Concerning to the recurrent PCa, a key treatment decision is based on whether the disease is only localized in the prostate fossa. If the sites of cancer in the early phase of recurrent disease were known, patients would be treated properly, leading to fewer side effects, a better prognosis with curative approache, and reduced treatment cost. Nuclear medicine imaging has been considered a reliable technique to be used with this purpose and an important aspect of the nuclear imaging that should be understood is that this type of imaging demonstrates physiology rather than anatomy [4, 6, 10, 11].

PET is a nuclear medicine technique for tumor imaging. The radiopharmaceutical 18F-FDG was firstly introduced to image brain tumors. Along the time, this radiopharmaceutical has been widely accepted and it was considered a highly effective and successfully way to image several types of cancers. In consequence, investigations using 18F-FDG were performed to evaluate the use of this radiopharmaceutical in the diagnosis of the PCa. Unfortunately, in general, the PCacan not be imaged with this radiopharmaceutical. This poor performance of 18F-FDG is mainly related to the low glucose metabolic rate in the PCa, as well as, a relevant excretion of the radiopharmaceutical into the adjacent urinary bladder. Moreover, it is well known that the ability of FDG-PET to detect cancer is based on an increased expression of cellular membrane glucose transporter and enhanced hexokinase II enzyme activity within the tumor cells, where the 18F-FDG undergoes enzymatic transformation to FDG-6 phosphate [10, 11].

Due to the limitations to use the 18F-FDG to detect PCa, other molecules to be labeled with a radionuclide, to be utilized as PET-radiopharmaceuticals, have been investigated with this purpose. Choline is a substrate for phosphatidylcholine, which is incorporated into cell membrane phospholipids, and is not dependent on cell proliferation and this molecule can be labeled with 11C or 18F for detection. 11C-choline has been shown to be superior to 18F-FDG to detect PCa, in part due to its negligible urinary secretion. 11C-choline PET has been shown to be able to localize primary PCa to the fossa of the prostate gland in up to 86.5% of patients and localize lymph node spread in up to 81.8% of patients [10, 11].

Another molecule, acetate, as 18F or 11C-labeled acetate, which is involved in cytoplasmic lipid synthesis, has been investigated to detect PCa. The retention of radiolabeled acetate in PCa cell lines has been shown to be related to fatty acid metabolism and enhanced beta-oxidation pathway. As PET-labeled acetate has minimal urinary activity, it is considered very suitable for evaluation of local prostatic disease with a high sensitivity for PCa lesions. When compared with 18F-FDG-PET for detection of primary tumors, there is a markedly increased sensitivity of 11C-acetate PET compared with 18F-FDG-PET, and the uptake of 11C-acetate is higher if the PSA is >3 ng/mL [10, 11].

The considerations about the early detection of the PCa is necessary, due to, there is considerable variation in the likely side effects and risks of long-term consequences such as urinary incontinence (UI) and erectile dysfunction (ED) in patients with PCa. With the early diagnosis there is an expectation of curing cancer, minimizing the risk of UI and ED and increasing the quality of life of the patient [38-41].

In general, radical prostatectomy (RP) is a curative and appropriated therapy for any patient whose tumour is clinically confined to the prostate, has a life expectancy of 10 years or more, and has no serious co-morbid conditions that would contraindicate surgery. Other factors affecting treatment decisions include patient factors, such as (i) Current symptoms (International Prostate Symptom Score, urinary flow rate), (ii) Current age (preference under the age of 70 years), (iii) Concurrent illnesses may determine suitability or not for surgery, (iv) Patient preference (psychological factors including patients ideas, concerns and expectations). Tumor/cancer factors, such as (a) Grade of tumour (the "aggressiveness" determines the risk of relapse), (b) Stage of tumour (determines radical of palliative approach), (c) Chance of response to treatment, (d) Chance of recurrence, and (e) Possibility of second curative treatment modalities if the first treatment fails must be also considered [6, 34, 38-41].

It is also important to consider that the risk of death under the anaesthetic for a RP is about 1 in 250 patients. The procedures used in the surgery become technically more challenging when the patient is overweight or obese and the risks of surgery increase. Improved knowledge about the anatomy of the organs of the pelvis and the muscles of the pelvic floor and the functions related to them had resulted in major improvements in this surgical technique [38-41].

Radiation therapy (RT) is another option for treatment of PCa. RT uses high-energy X-rays or other types of ionizing radiation to try to kill the cancer cells in various organs/tissues. There are mainly two types of radiotherapy: (i) External radiotherapy that uses a source of ionizing radiation that is outside of the body and (ii) Internal radiotherapy that uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer (brachytherapy). The external radiotherapy is a complex procedure and requires the patient to make a number of steps, as (i) positioning and immobilization of the patient, (ii) localization of the tumor, (iii) determination of the size of the tumor, (iv) delineation of the target (tumor) and critical tissues structures in the neighborhood, (v) dose prescription, (vi) type of ionizing radiation, (vii) treatment planning, (viii) simulation and verification of the treatment and (ix) evaluation.Concerning to the brachytherapy to the PCa, several radioactive seeds (in general with iodine-125] are implanted into the prostate gland with the aim to irradiate the tumor. These seeds are not removed and will be permanently in the prostate. As the iodine-125 emits low level energy electromagnetic radiation, the energy of the radiation is deposited in the prostate, treating locally the tumor [4].

Various severe complications following RT can occur and these complications depend on the type of the procedure used in the treatment. In addition, clinical complications, such as UI and ED have also been associated with the RT [6, 14, 40, 42].

In Figure 3 is shown some modalities of treatment for PCa and possible adverse effects associated with some of these treatments.

Figure 3. Modalities of treatment for the prostate cancer and possible adverse effects associated.

As presented before, UI and ED are undesirable side effects normally associated with the RP and RT due to the damage of the muscles of the pelvic floor. [26, 38, 39, 43]

UI has a prevalence ranging from 5 to 60 per cent. UI after RP is the most bothersome complication of this operation and has a major impact on the quality of life and it is therefore of the utmost importance to minimize its prevalence after this kind of surgery. In the clinical routine with the patient that was submitted to treatment to PCa, it is verified that the UI is an unpleasant condition [21, 24, 26].

The types and characteristics of UI secondary to PCa are (a) Stress UI, which is mainly associated with RP; (b) Urge incontinence, which is associated with RT and consists of a strong, unpleasant and sudden urge to urinate, with burning sensation or irritation in the bladder; and (c) Mixed incontinence, which affects mainly older patients on radiation and/or hormone therapy [21, 24]

In addition to the functional problem of the UI, this clinical condition causes a psychosocial disorder characterized by distress. Moreover, this is potentialised and augmented by the inability of the patient to perform habitual activities. Furthermore, the impossibility of controlling leakage and the resulting feeling of regression, and the inability to overcome the fatigue resulting from the interruption in the number of hours and the quality of sleep in the case of nocturia and anxiety increase dissatisfaction. In consequence, a restrictive social situation can be usually observed, characterized by shyness, shame from the leakage, and social stig-matization and isolation. Additionally, UI may trigger an undesirable, obsessive and strong psychological behavior related to the control of leakage of urine and of associated odors. These factors can increase the anxiety and to cause a reduction of the social life of the patient. Additionally, UI may trigger an obsessive and strong psychological behavior related to the control of leakage and odors. These factors can contribute to cause a reduction of the social life of the patient [6, 14, 20, 24, 42].

The impact of UI on the quality of life of the PCa patient is determined by the self-perception of the severity and the disruption of daily activities caused by the symptoms. An important consideration is that the cases of UI and ED (and other sexual dysfunctions, see Figure 3] recorded in clinics seem to be much higher than the number described in the publications. This discrepancy could be attributed to the great variability of definitions, measurement instruments, and manners of assessing UI. If a good interview with the patient before the treatment of the PCa is not performed, it is also difficult to determine whether the symptom is a result of the treatment of the disease or of the natural involution that would occur with age. Moreover, there is a fatalistic and resigned attitude that makes the patients hide or mask the symptom from the professional or the professional is not prepared to obtain the informations that are relevant to the clinical conditions of the patient [6, 20, 24, 42].

ED, in general, is usually due to a multifactorial etiology, comprising organic, psychological, or mixed aspects, and may often require a multidisciplinary approach for assessment and treatment. Organic causes encompass vascular, neurologic, hormonal, as a result of medications, pelvic surgery (mainly RP), RT, diabetes or mixed factors. In general, any condition that can cause damages to the nerves or impair blood flow in the penis may lead to ED. Pelvic surgery (especially RP and bladder surgery for cancer) might damage cavernous nerves and arteries near the penis, causing ED [23, 30, 39].

Penile erection is the consequence of a complex neurovascular process in which nerves, en-dothelium of sinusoids and blood vessels, and smooth muscle cells are involved. Several central nervous and peripheral transmitters and transmitter systems participate in the process and the nitric oxide (NO) is the main mediator of penile erection. It is produced by a group of enzymes called nitric oxide synthase (NOS) which utilizes the amino acid L-argi-nine and molecular oxygen as substrates to produce NO and L-citrulline. The endothelial NOS is constitutively expressed within the vascular system, it is tightly regulated and produces physiologically relevant levels of NO.The investigations about the NO, that can readi ly cross plasma membranes to enter target cells, and its functions as a mediator synthesized and released from the vascular endothelium and as a neurotransmitter in inhibitory nerves innervating the penis represented a breakthrough in the comprehension of the neurophysio-logical basis of erection. Moreover, the synthesis of NO and the consequences of NO binding to soluble guanylylcyclase is essential for the erectile process [44, 45, 46].

Impaired erectile function, or the total inability to maintain or achieve sufficient penile rigidity for satisfactory sexual intercourse performance, it was firstly used as a definition of impotence. On 1992, it was recommended that the term "erectile dysfunction" replace the term "impotence," but, sometimes, the two terms have been used interchangeably. The term ED is more precise and eliminates the confusion of multiple meanings and connotations associated with the word impotence. ED is defined as a "consistent or recurrent inability of a man to attain and/or maintain penile erection sufficient for sexual activity". The condition must be present for a minimum of 3 months to establish the diagnosis. The exception to this is when ED is preceded by trauma or pelvic surgery [47, 48, 49]

In addition, penile erection involves a complex interaction between the central nervous system and local factors. The penis is innervated and regulated by autonomic (sympathetic and parasympathetic) and somatic (sensory and motor) nerve fibers. Overall, erection is a neuro-vascular event modulated by psychological and hormonal factors. The economic burden of ED is not just limited to the cost of diagnosis and treatment. Subtle impacts on the society that are difficult to quantify are (i) lost time at work, (ii) decreased productivity of the patient due to distress, (iii) impact on the partner and family and (iv) alteration of the social interactions. The comprehensive knowledge and the understanding of these conditions have also reflected in the number of papers published in important scientific journals that have increased along of the years [27, 38, 39, 41, 46].

Reports of studies describing ED after RP have shown a range from 29% to 97.5% with less ED occurring in younger men. Men with ED may suffer from depression and low self-esteem, and experience difficulties establishing and maintaining relationships. Treatment regimens currently available for ED include psychotherapy, sex therapy, oral pharmacological agents, androgen replacement therapy, intraurethral therapy, intracavernosal injections, several procedures related to the physiotherapy and surgery [27, 38, 39, 41, 50].

The pelvic floor muscles, besides other functions, play an important role in sexual activity and contractions of the ischiocavernosus and bulbocavernosus muscles produce an increase in the intracavernous pressure and influence penile rigidity. The bulbocavernosus muscle compresses the deep dorsal vein of the penis to prevent the outflow of blood from an engorged penis. The procedures of the physiotherapy, associated with a interdisciplinar team, including exercises for the muscles of the pelvic floor muscle only or associated with mano-metric biofeedback, electrotherapy, vaccum pumps can be used successfully in various patients with ED [20-26]

In addition, it is highly desired to consider that beneficial effects of pre- and postoperative pelvic floor interventions (RT or RP) using physiotherapy procedures, since both the duration and degree of UI after RP decrease in these case [24, 51-53].

When a patient with PCa is referred to undertake physiotherapy procedures before the surgery or radiotherapy, it is possible to teach him about the perception of the muscles of the pelvic foor, facilitating the performance of exercises involving these muscles associated with an ideal breathing, just after the RP or RT [6, 22-24].

As it is possible to see in the Figure 3, besides the ED, another clinical conditions related to the sexual functions can appear in the patient submitted to a RP, as the loss of ejaculation and the decrease of the libido and orgasm [6, 27, 39, 41].

The interventions related to the physiotherapy will contribute to aid the patient to live your sexuality. Moreover, it is important to show to the patient that sexuality is not only genitali-ty, but it goes beyond the limits of genital impulse and is characterized as a strong experience of human personality [6, 13, 27, 39, 41].

Several options of treatment are available to treat ED, as psychosexual counseling, medication, use of physiotherapy (exercises to the pelvic floor muscles, electrotherapy, acupuncture and external vacuum devices), intracavernous injection therapy, vascular surgery, and use of a penile prosthesis. The etiology of the ED, the acceptability for the patient, the available information about methods and the success rate have been used to determine the choice of intervention. The clinical interventions used in the physiotherapy provide noninvasive methods that are easy to perform, painless, and inexpensive [6, 39, 41, 50, 51].

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