Prostatic cancer is the first tumour for incidence (29% of all cancers) and the second cause of cancer death (13% of all cancers, second to lung cancer only) for men in western countries.
However, the natural history of the tumour may be slow. Nearly one man out of 6 will be diagnosed with prostate cancer, but the disease mortality is 3%. So it is estimated that only 20% of men with a prostate cancer diagnosis will die of the tumour, while the remaining 80% will die with the tumor, but for another reason.At the age of 80 about 20-40% of men have some foci of prostate cancer. The disease risk is increased by a diet rich with fat.Recently it has been shown that a virus might promote the onset of prostate cancer.
The course of the disease is depending upon the grade of the tumour. Prostate cancer grading is based on a score (Gleason), going from 2 (well differentiated tumor) to 10 (undifferentiated tumor). In recent reports, it has been established that for clinical purpose the histology grade should be limited to Gleason 5 (low grade), Gleason 6 (low-intermediate grade), Gleason 7 (intermediate grade) Gleason 8-10 (high-very high grade). Fifteen year mortality for untreated cancer is 9% for low grade, 28% for intermediate grade, and 58% for high grade disease.
In younger patients, life expectancy for untreated cancer is decreased by 4-5 years and 6-8 years for intermediate and high grade, respectively. In patients younger than 65 years with localized cancer (no spread to lymph nodes and no distant metastasis), mortality for untreated cancer can be as high as 65%.In my opinion, patients with prostate cancer younger than 70 years should undergo definitive treatment; patients between 70 and 75 years may receive definitive treatment according to grade and stage of disease, and to general health status; palliative treatments should be reserved for patients older than 75 years. Surgery should be offered to all patients with intermediate or high grade localized cancer and a life expectancy at least of 10-15 years.

Diagnosis

PSA
Prostate cancer is asymptomatic for a long time. When symptoms like urinary obstruction or bone pain arise, the disease is too advanced and beyond the chance of definitive therapy.
The diagnosis of prostate cancer has changed dramatically in the last fifteen years, due to the introduction of the most useful biological marker in oncology: the Prostate Specific Antigen (PSA). The PSA is a protein that, for practical clinical use, can be considered of exclusive prostatic origin. Usually the concentration is very high in prostatic secretions and in the semen , and extremely low in the circulating blood.. PSA is produced by normal, hyperplasic, and cancer prostatic cells (also from distant metastasis). Any change of prostatic cellular structure can induce an elevated PSA, due to increased "leakage" of PSA from the prostatic cells to the blood vessels. Acute, and sometimes chronic infection of the prostate may increase the PSA, maybe for increased vessel permeability during inflammation. An indwelling catheter, transurethral procedures, and prostatic massage can all cause a transient elevation of PSA. Prostatic biopsy obviously produces a temporary rise of PSA. PSA should be measured again only 4-6 weeks after prostatic biopsy.
The half-life of PSA in the blood is about 3 days. Benign prostate enlargement can cause a moderate PSA increase, especially in very large prostates.
The main clinical interest of PSA is in the diagnosis, staging, prognosis and treatment evaluation of prostate cancer.
For early prostate cancer diagnosis, every male at the age of fifty should start PSA measurement on annual basis. The screening should start at the age of forty for afro-americans and for patients with a family history of prostate cancer. The normal reference range of PSA is between 0.1 and 4.0 ng/ml. When PSA is beyond 4.0 ng/ml, the chance of having a prostate cancer is 33-51%, according to different series and/or the biopsy method. In the PSA range between 4.0 and 10.0, the incidence of cancer is 24-47%.
Some Authors have proposed to decrease the cut-offto 2.5 ng/ml. When PSA is between 2.5 and 4.0%, the incidence of cancer is 24-27%. Though an increased number of negative biopsies would be performed with this limit, a higher number of cancers would be detected, particularly in young patients.
Of course these data are not absolute. For instance, a PSA value of 3.9 ng/ml, though in the normal range, should anyhow be investigated.
For diagnostic purpose, it is very important the way the PSA changes along time (PSA velocity). An increase of 1ng/ml/year is considered suspicious. A PSA that in 2 years interval moves from 2.0 to 6.0, is probably more wary of a PSA which has been stable around 9 ng/ml in the last 5 years, in a prostate with a very large adenoma.
The free PSA is a portion of the total PSA very sensitive for prostate cancer diagnosis. A ratio of free and total PSA below 18% is suggestive of prostate cancer, in the range of total PSA between 2.5 and 10.0 ng/ml.
New molecular forms of PSA are under investigation, with promising results.

Digital rectal examination (DRE)
Digital rectal examination (DRE) is a simple, fast and cheap test for prostate cancer diagnosis, thou less sensitive than PSA. With DRE only, up to 45%-70% of prostate cancers can be missed. However, since some tumors may present with normal PSA, DRE should be performed in every man after 50.

Transrectal ultrasound (TRUS)
A good imaging of the prostate can be obtained through transrectal ultrasound (TRUS). Usually cancer can be seen as a hypoechoic (darker than the surrounding tissue) nodule or peripheral area.

Nevertheless, up to 40% of cancers are not seen by transrectal ultrasound. The tumor extension may be underestimated by TRUS. When the disease is extracapsular (it has reached and penetrated the prostate capsule), TRUS is not able to predict it in 40-50% of cases. However, when an extracapsular disease is seen by ultrasound, the tumor has a 80-90% chance of extendingbeyond the prostate capsule. Though it has some limits, transrectal ultrasound can be helpful for the detection and staging of prostate cancer.

Magnetic Resonance (MR) with Endorectal coil
This recent and promising technique for detecting and locally staging prostate cancer is expanding and becoming very reliable. In the next future it could become a key point for decision making in the treatment of prostate cancer.
I personally prescribe the test to all men candidate to radical prostatectomy.
With endorectal MR there is a high definition imaging of the prostate and surrounding tissues.
The latest instruments can provide a metabolic analysis of the prostatic tissue, with special attention to Choline and Citrate concentrations, that can be altered in tumors.

Prostate biopsy
Prostate biopsy is the only way to prove the presence of a prostate cancer. The biopsy is performed with a specially designed cutting needle; with a double advancement a tiny sample of prostatic tissue is obtained. The biopsy is performed through a transrectal (the needle is passed through the rectal wall) or a transperineal (through the skin between the scrotum and the anus) approach.
Digital guided biopsy is outdated and the procedure is performed today under transrectal ultrasound control. In most western countries the transrectal approach is preferred. Since a large percentage of tumors are not clearly visible by ultrasound, the samples (cores) are obtained according to random schemes. Of course all hypoechoic lesions are included in the biopsy.
Some authors recently have suggested evaluation of prostatic tissue through Doppler transrectal ultrasound, to identify areas with increased blood supply, suspicious for cancer. Further studies are needed to confirm this approach.
Sextant (with 6 cores) transrectal biopsy has been widely used in the nineties. However, in the last decade several studies have questioned the sextant technique, and new protocols with increased number of cores have been introduced. Six cores are not considered enough for adequate prostate cancer detection, especially in large prostates. Nowadays a good prostate biopsy should include at least 8 cores, with optimal number of cores between 10 and 12. In patients with increasing PSA and one or more negative biopsies, some urologist propose a saturation biopsy, with protocols that can obtained sometimesmore than 30 cores.
Personally since 1997 I´ve useda "fan" technique, with 12 cores obtained through a perineal approach. The results in more than 2000 patients are satisfying. Prostate cancer has been detected in 47% and 45% of cases with PSA above 4.0 and PSA between 4.0 and 10.0 ng/ml, respectively.
Since in my series nearly half the patients with PSA above 4.0 ng/ml have a prostate cancer, I recommend a 10-12 core biopsy in all patients with increased PSA.
Prostate biopsy is an office procedure. With transrectal approach the local anesthesia is not strictly required, but several studies have shown that with local anesthesia, the procedure is better accepted.
The local anesthesia is needed with transperineal approach. Temporary haematuria (blood in the urine) for 7-10 days and haemospermia (blood in the semen) for 2-3 months are not uncommon after prostate biopsy.

PrimaryTumor (T)

TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Clinically inapparent tumor not palpable nor visible by imaging

• T1a Tumor incidental histologic finding in 5% or less of tissue resected (in prostatectomy)
• T1bTumor incidental histologic finding in more than 5% of tissue resected
• T1cTumor identified by needle biopsy (e.g., because of elevated PSA)

T2 Tumor confined within prostate

• T2a Tumor involves one-half of 1 lobe or less
• T2bTumor involves more than one-half of 1 lobe but not both lobes
• T2cTumor involves both lobes

T3 Tumor extends through the prostate capsule

• T3a Extracapsular extension (unilateral or bilateral)
• T3b Tumor invades seminal vesicle(s)

T4 Tumor is fixed or invades adjacent structures other than seminal vesicles: bladder neck, external sphincter, rectum, levator muscles,and/or pelvic wall.

Regional lymph nodes (N)
NX Regional lymph nodes were not assessed
N0 No regional lymph node metastasis (lymph nodes confined to the true pelvis)
N1 Metastasis in regional lymph node(s)

Distant metastasis (M)
MX Distant metastasis cannot be assessed (not evaluated by any modality)
M0 No distant metastasis
M1 Distant metastasis

• M1a Nonregional lymph node(s)
• M1b Bone(s)
• M1c Other site(s) with or without bone disease

Prostate cancer: Treatment.
After a prostate cancer diagnosis, accurate staging of the disease is essential. Local staging is achieved trough Digital Rectal Examination, Magnetic Resonance with Endocoil. Important staging factors are the value of PSA, the Gleason score, the percentage of positive cores in the biopsy, and the fraction of total cancers in all cores. The combination of these data can provide a reliable staging method. When PSA is below 10.0 ng/ml and Gleason score is below 7, the chances of having disease metastases to lymph nodes or to the bone is very low. All the other patients should undergo a CT or MR of the pelvis and a bone scan.
Occasionally some tumors are very small (less than 0.5 cc of volume) and with a Gleason score lower than 6. These tumors are considered not clinically significant, and can deserve watchful waiting, rather than aggressive treatment.
Scandinavian studies have proposed a watchful waiting for moderately aggressive tumors (Gleason score less than 7, PSA lower than 10.0 ng/ml). Though this approach can be reasonable in elder patients (70-75 years of age or older), recent data show that when patients with moderately aggressive disease are followed for 15-20 years, cancer mortality is higher than 50%.
Therefore we must be very cautious before proposing watchful waiting in patients of 65 years or younger.
When the disease is still inside the gland, it can be fully cured through surgical removal of the gland (radical prostatectomy). Since prostate cancer is usually slowly progressing, usually radical prostatectomy should be reserved to patients with at least 10 years of life expectancy (generally they are patients 70 years old or younger). In low grade tumors (Gleason score 5 or less) a conservative approach can be reasonable, since the chance of tumor progression at 15 years is rather low. Aggressive tumors (Gleason 8 or higher) may require radical prostatectomy in selected patients older than 70, as poorly differentiated tumors can grow rapidly and progress to metastatic disease in most patients in 5-6 years.
Open radical prostatectomy can be performed through a retropubic or a perineal approach. Preoperative hormone therapy has no influence on radical prostatectomy results, and today it is considered useless.
Radical prostatectomy is a well standardized procedure. The average blood loss is between 200 and 1000 cc. When the tumor doesn´t reach the prostate capsule, the erection nerves that run on the postero-lateral aspect of the gland, can be spared. However, even after a nerve-sparing procedure, some grade of erectile dysfunction can be present in 20-70% of cases.
Temporary stress urinary incontinence in not uncommon after the procedure., lasting form a few weeks to several months. After 6-12 months only 3-5% of patients have still some degree of incontinence.
Recently a new approach to radical prostectomy, laparoscopy, is expanding in western countries. The operation is performed through some small holes in the abdominal wall, with long and small instruments that are guided by a microcamera

The peritoneal cavity, or the pelvic space anterior to the prostate, are inflated with C02. The tissues are distended by the gas pressure. The whole procedure is done with a great magnification on a screen. The advantages are better anatomical details and control, the clear visualization of areas that can´t be seen with the open approach, a mini-invasive procedure, a lower blood loss (average 100-200 cc). The operation can be performed with conventional laparoscopy, or with robot assisted laparoscopy. The robot is a complex apparatus, with robotic arms, guided by a computer that reproduces the movements of the operator´s hands outside the body. The surgeon is sitting at a console, where he/she can have a three-dimensional view of the operating field. Small and versatile instruments perform the procedure inside the body. The use of the robot is especially spread in US, where 75% of prostatectomies are performed by robot assisted laparoscopy.
The recovery to normal activities is usually faster after laparoscopic radical prostatectomy. The functional results (about continence and potency) are at least equal to the ones of open surgery. The first oncological results (no evidence of disease) at five years are comparable to the ones obtained by excellence centers with open radical prostatectomy. Disadvantages include a long learning curve, especially for laparoscopy beginners, and a moderately longer operative time. The learning curve is shorter with the use of the robot.
If we include only studies with more than 100 cases, more than 10,000 laparoscopic radical prostatectomies have been reported in literature. Probably the number of procedures performed all over the world is 3-4 times higher. The results are very encouraging and this mini-invasive procedure could become in the next future the standard of prostatic cancer surgery.
Today, the surgeon should offer to the patient the technique he feels confident in, according to his experience and skills.
When after radical prostatectomy the surgical margins of the prostate are positive for disease (the cancer reaches the external limit of the surgical resection), there is a higher risk of local recurrence of tumor. In this group of patients, an early radiotherapy (60 Gy) can appreciably improve prognosis and survival.
The cure rate after radical prostatectomy is depending upon several factors, including stage at final pathology, Gleason score, preoperative PSA, preoperative PSA velocity, surgical margin status.
After radical prostatectomy, patients are followed with PSA measurement every 3 months.
At 10 years, in nearly 70% of patients no significative PSA (less or equal to 0.2 ng/ml) can be detected, 20% of patients have increased PSA without any other clinical sign of disease, and 10% of patients have local recurrence or metastatic disease.
A PSA is 0.4 ng/ml or above means recurrence of disease. When the PSA reaches this value at least 18 months after surgery, the patient is likely to have a local recurrence, rather than distant metastasis. When a local recurrence is present, still 30-45% of patients can be successfully treated with local radiotherapy.

Radiotherapy
High energy radiation can treat prostate cancer. The treatment usually last a few weeks, and it is well tolerated. New techniques allow 3-dimensional imaging of the target (the gland), with more precise, high dose energy and decreased side effects on surrounding organs (mainly bladder and rectum/anus)



Brachitherapy is another radiation treatment modality which is becoming popular. Brachiterapy is performed releasing some radioactive seeds in the prostate. The optimal dose is evaluated through CT scan-based 3-D imaging of the gland. Ten-year results are promising, apparently equivalent to the ones of conventional external beam radiotherapy. However the risk of urethral strictures and rectal fistulas is higher with brachitherapy compared to external radiotherapy.
Main side effects of external radiotherapy are bladder and rectum irritative symptoms, at times with diarrhoea, increased urinary frequency. In only 5% of cases these symptoms become chronic.
Some degree of erectile dysfunction can occur after radiotherapy in 40-70% of patients.
Even several years after radiotherapy severe haematuria (blood in the urine) can occur.
Some authors have proposed to increase radiotherapy efficacy with concomitant hormone therapy, to be continued for 3 years. The aim of the combined treatment is to decrease the tumor volume and to increase radiosensitivity of tumor cells. This approach has proven to be more effective in aggressive or locally advanced prostate cancers.
Radiotherapy results are not easy comparable to the ones of radical prostatectomy, since after radiotherapy  PSA doesn´t reach the same levels as after surgery. PSA reaches the lowest concentration (nadir) usually in 18-24 months.  Since prostate cancer is often a slowly progressing disease, results evaluation needs a followup of 10-15 years. Disease-free survival after radiotherapy for curable prostate cancer is 75-95% at 5 years and 55-85% at 10 years, according to literature. Anyhow, about 50-60% of patients after radiotherapy have still cancer at prostate biopsy; this group is at increased risk of progression and disease related death.
The results of radiotherapy for locally advanced tumors (extending beyond capsule, without distant metastases) are less encouraging, with 15-30% survival at 10 years.
Cryotherapy has been proposed to treat prostate cancer recurrent after radiotherapy failure. However, a long followup is needed to assess the results and the risks of the treatment.
The experience of high frequency radio waves application (HIFU) for prostate cancer is stll preliminary.
Though radical prostatectomy is feasible after the failure of radiotherapy, the risk of complications, including urinary incontinence, is higher

Hormone therapy

Though the effects of androgen deprivation on prostate cancer are well known, hormonal therapy should be considered a palliative treatment in very old or with metastatic disease patients, rather than a definitive therapy.
Oestrogen therapy has been almost abandoned for serious cardiovascular side effects.
Several drugs are today available (Leuprolide, Goserelin, Buserelin, Triptorelin) for inhibition of testosterone secretion (Luteining Hormone Releasing Hormone - LHRH analogues). They are available in monthly or quarterly administration. Usually hormone therapy is well tolerated. Side effects can include erectile dysfunction, mood changes, loss of muscle tissue, bone demineralization, and hot rushes.
Other drugs used for hormone therapy are antiandrogens (flutamide,  bicalutamide,  nilutamide, cyproterone acetate). They can be used together with LHRH analogues or as monotherapy. Though side effects on sexual function are less severe, androgen monotherapy for prostate cancer is not considered a standard therapy.  The association between an LHRH analogue and an antiadrogen is known as "Total Androgen Blockade", and it is still debated. Some papers have reported an increase of median survival of 7 months with total androgen blockade, but a recent review of the literature leaves the problem still open. A large study of EORTC didn´t show any significant advantage when an antiandrogen was added to the therapy with LHRH analogues.
Intermittent hormone therapy has been proposed. The rationale is based upon the fact that after an interval of time some cell clones become resistant to hormone deprivation. Interrupting the hormone therapy might increase biological competition between hormone dependent and not hormone dependant cells, delaying the onset of hormone refractory disease. Long term randomized trials are required to asses the efficacy, if any, of this approach.
The association of hormone therapy and radiotherapy seems to improve survival for locally advanced prostate cancer.
Generally hormone therapy is given to patients with metastatic disease, or not otherwise treatable, or after the failure of surgery and/or radiotherapy.
For metastatic disease, early hormone treatment delays disease progression and prolongs survival, compared to delayed (at the onset of symptoms) treatment.  It is uncertain if elder patients with localized disease could benefit from early hormone therapy. Again, in a study from EORTC, in these patients there is no results´difference between early and delayed hormone therapy.

How I treat prostate cancer
I consider radical prostatectomy the best therapeutic option to obtain definitive cure for intracapsular prostate cancer. In patients younger than 71 years and with Gleason score 6 or higher, unless there is clinically insignificant cancer, radical prostatectomy is my first choice.  For patients between 71 and 75 years old, radical prostatectomy can be an option in motivated patients, in patients with long life expectancy, or with high grade cancer (Gleason score 7 (4+3), or 8-10) deserving aggressive therapy, since this last group could experience disease progression within 5-8 years.
In patients with Gleason score 5 and localized prostate cancer, radical prostatectomy is a good option for patients 59 years old or younger, while expecting approach can be reasonable only for patients older than 60 years, due to the fact that cancer progression is unlikely to occur on a long time period. These patients, however, must be followed strictly to assess if the disease is very slow, or if there is an evolution trend. When the tumor is localized, radiotherapy is a good option for patients of age 75-80,  for patients between 70 and 75 years with Gleason score 7 (3+4) or less, or for patients with extensive extracapsular  disease, where the chance of surgical cure is low. Hormone therapy is my treatment for metastatic disease, or recurrence after radical prostatectomy and/or radiotherapy. In very old patients it can be an option, to start immediately for advanced disease. The hormone treatment can be delayed in very old patients with localized asymptomatic prostate cancer.