Treatment for Localized Prostate Cancer

Selection of the appropriate treatment requires assessment of the tumor's potential aggressiveness and the general health, life expectancy, and quality of life preferences of the patient. The treatment outcomes in patients may be influenced by the malignant potential of the tumors as well as by the treatment used. 

Conservative Treatment: 

Watchful Waiting refers to monitoring the patient until he develops metastases that require palliative treatment.  

• Watchful waiting has been reserved for men with a life expectancy of less than 10 years and a low-grade (Gleason score 2 to 5) prostate cancer.

Active surveillance allows delayed primary treatment if there is biochemical or histologic evidence of cancer progression. 

• Active surveillance is being evaluated as a management strategy in younger patients with low-volume, low- or intermediate-grade (up to Gleason score 3 + 4 = 7) tumors to avoid or to delay treatment that might not be immediately necessary.
• Monitoring of the patient for progression for either watchful waiting or active surveillance patients are usually observed with semiannual PSA determinations, DRE, and annual biopsies.  
• Intervention is recommended if Gleason pattern 4 or 5 is present, more than two biopsy cores are involved, or more than 50% of a biopsy core is involved. 
• Progression is more likely in patients who have cancer present on every biopsy procedure. 
• The absence of cancer on repeated biopsy significantly decreases the likelihood of progression. 
• Biopsy criteria used in active surveillance have been reported to be more accurate than PSA criteria in predicting progression. 
• No study has found DRE or imaging studies to independently predict progression.
• In most studies of active surveillance, approximately 25% to 50% of patients, depending on their individual risk factors, develop objective evidence of tumor progression within 5 years.  
• Presently, no tumor marker can identify indolent tumors with certainty.
• Additional clinical and laboratory research are needed to define the parameters for safe use of active surveillance in younger men, including the appropriate selection criteria, follow-up procedures, and trigger points for intervention.
• All prostate cancer patients are at risk for progression.
• If the PSA level is rising, the DRE suggests tumor growth, or surveillance biopsy specimens show evidence of increased involvement by cancer, treatment should be instituted.
•  Patients may change their minds about remaining on an active surveillance protocol; therefore the physician should review management options on follow-up visits.
• In discussing treatment for prostate cancer, it is important to consider patient factors such as age and general performance status as well as tumor factors such as Gleason score, initial serum PSA, and estimated clinical volumes/stage of the tumor. 
• If a patient has less than a 50 percent chance of surviving 10 years, it is difficult to measure the positive effect of treatment. 
• The side effects of different therapies also have to be considered. It is optimal when patients come to a treatment decision based on consultation and input from both surgical and radiation oncology services.

The current treatment paradigm

• Multiple guidelines endorse active surveillance for low-risk prostate cancer, but concerns regarding biopsy under-sampling and under-staging have limited its acceptance.

• Today, more than 90 percent of these low risk patients undergo immediate treatment such as radical prostatectomy or radiation, despite less than a 3% chance of low risk disease progressing 

Genomic Prostate Score (GPS)

• The Oncotype DX prostate cancer test (Genomic Prostate Score) is a biopsy-based genomic test that, when combined with other measures, can be used to predict the aggressiveness of prostate cancer
• The GPS test is a standardized, validated biopsy-based test that measures the level of expression of multiple genes across multiple pathways that predict aggressive prostate cancer

more on genomics: 

Radical or complete prostatectomy

• This is the treatment choice for patients with organ-confined disease and a life expectancy of more than 10 years. Generally, age 70 is used as a relative cutoff for strongly recommending surgery and 75 years of age is certainly the upper accepted end of the age limit. 
• The patient goals are the cure of his cancer (survival), the preservation of his potency, and to remain continent.  Patients want all three outcomes. 
• The indications for LRP and RALP are identical to that for open surgery (patients with ≤ clinical stage T2 with no evidence of metastasis either clinically or radiographically.
• The radical perineal prostatectomy is associated with reduced blood loss as the dorsal venous complex is not divided. It may be the preferred approach in very obese men or in those with a history of abdominal or pelvic surgery where significant retropubic scarring and fibrosis are suspected.
• The disadvantages are that it does not provide access for a pelvic lymph node dissection, there is a higher rate of rectal injury, and there is occasional postoperative fecal incontinence that does not occur commonly with other approaches.
• It is more difficult to spare the cavernous nerves through the perineal approach.The open retropubic approach is preferred by many urologists because of their familiarity with the surgical anatomy, the lower risk for rectal injury and postoperative fecal incontinence, the wide exposure and ready access provided for pelvic lymphadenectomy and prostate excision with preservation of the neurovascular bundles, and the lower risk for positive surgical margins.
• Significant urinary incontinence may be encountered in up to 4 to 8 percent of patients, and bladder neck contractures can occur in 2 to 6 percent of patients. 
• Surgical mortality is less than 0.2 percent but 1 to 2 percent of patients may develop pulmonary emboli. 
• When laparoscopic prostatectomy (LRP) is performed by a skilled laparoscopic surgeon, reported incontinence and anastomotic stricture rates are comparable to those achieved with open surgery. 

• It has been claimed that nerve sparing is equivalent or even better with laparoscopic surgery, but direct comparisons and validated results are lacking. 
• The early reported rates of positive surgical margins have been higher with laparoscopic prostatectomy, and the adequacy of cancer control is as yet uncertain because of lack of long-term results.
• Remotely controlled laparoscopic surgery or the robot-assisted laparoscopic prostatectomy has becoome popularized because of its greater technical ease for the surgeon, especially for tying sutures and performing the vesicourethral anastomosis.
• The availability of three-dimensional visualization is an advantage over standard laparoscopic techniques.
• Early reported results are favorable, but have not been validated.
• It is also more difficult to perform a lymph node dissection with laparoscopic approaches.
• Pelvic lymphadenectomy is optional in patients at low risk for lymph node metastases.

Postoperative patient care

• Patients should ambulate with assistance beginning on the afternoon or evening of surgery.

• The catheter may be removed 3 to 21 days after surgery, depending on the integrity and the amount of tension on the vesicourethral anastomosis. The more days the catheter is in place the greater the risk of urinarty tract infection (CaUTI).  Removal of the catheter before 7 days is associated with a 15% to 20% risk of urinary retention - View Protocol.  View all CaUTI resources at www.cautichallenge.com

• After the catheter has been removed, Kegel exercises should be initiated. A protective pad is used until complete urinary control is achieved. The postoperative serum PSA level should be undetectable by 1 month after the operation. 
• The return of urinary continence is associated with the patient's age: approximately 95% of men younger than 60 years can attain pad-free urinary continence after surgery; 85% of men older than 70 years regain continence. Few require implantation of an artificial urinary sphincter or a sling procedure for stress urinary incontinence.
• The return of erectile function after radical retropubic prostatectomy correlates with the age of the patient, preoperative potency status and the extent of nerve-sparing surgery.
• In candidates in whom preoperative potency is normal and bilateral nerve-sparing surgery can be performed, up to 95% in their 40s, 85% in their 50s, 75% in their 60s, and 50% in their 70s can attain recovery of erections sufficient for penetration and intercourse. In most instances, erections are not as good as they were preoperatively.
• In patients, erections usually begin to return as partial erections 3 to 6 months after surgery and may continue to improve for up to 3 years or more.  

External beam radiation therapy

• This is an option for localized prostate cancer and is the treatment of choice for T3 disease. 
• There is evidence from prospective, randomized trials that dose escalation and three-dimensional definition improve results considerably.
• External beam radiotherapy involves the use of beams of gamma radiation, usually photons, directed at the prostate and surrounding tissues through multiple fields.
• The most sophisticated form of 3D-CRT, called intensity-modulated radiation therapy (IMRT), can provide localization of the radiation dose to geometrically complex fields.
• Heavy-particle therapy is another form of 3D-CRT in which the radiation beam can be virtually “stopped” within the tissue, allowing high doses of radiation to be delivered to a localized region. 
• Proton beam therapy is more expensive than other forms of 3D-CRT, and limited long-term results have been reported.
• Currently, doses of 76 to 80 Gy or more have been shown to improve cancer control.
• Low-risk patients are now frequently treated with 70 to 72 Gy, intermediate-risk patients with 75 to 76 Gy, and high-risk patients with 80 Gy or more. Doses above 75 Gy are now considered to be indicated; however, doses above 80 Gy have not been demonstrated to be beneficial.
• In general, it is administered in divided doses ranging from 70 to 80 Gy and is well tolerated. 
• Approximately 3 to 5 percent of patients will experience persistent rectal or bladder symptomatology and greater than 50 percent of patients develop erectile dysfunction within 2 years. Hematuria or hemorrhagic cystitis is a late development in a small percentage of patients. Techniques of conformal therapy have reduced unwanted radiation to the bladder and rectum.
• CT imaging is considered the standard imaging modality for 3D-CRT and 3D-IMRT, but CT is less precise than MRI.
• A prior transurethral resection of the prostate is a relative contraindication to brachytherapy and external beam radiation therapy because the prostate does not hold the seeds well, and radiation after transurethral resection of the prostate is associated with an increased risk for urethral stricture. 
• The presence of severe obstructive urinary symptoms is also a relative contraindication because of the risk for acute urinary retention, which is an even greater risk in patients treated with brachytherapy. 
• Another relative contraindication is inflammatory bowel disease.
• Approximately half of patients develop erectile dysfunction after radiotherapy for prostate cancer. This is caused by injury to the vasculature of the cavernous nerves and to the corpora cavernosa of the penis, usually beginning about 1 year after the completion of treatment. 
• Younger patients with good baseline erectile function are more likely to retain adequate erections. PDE-5 inhibitors are useful in ameliorating the erectile dysfunction associated with radiotherapy. Lower doses of radiation to the penile bulb have been investigated as a means of minimizing radiation-induced erectile dysfunction. The use of adjuvant hormone therapy also adversely affects erectile function.
• Evaluation of the outcomes of radiotherapy is challenging because cancer cells are not killed immediately after exposure to ionizing radiation. Rather, they sustain lethal DNA damage but do not die until their next attempt to enter into cell division. The PSA level gradually decreases for up to 2 to 3 years after the completion of radiotherapy. 
• The PSA level is usually monitored at 6-month intervals until it reaches a nadir. In patients treated with external beam radiotherapy, the prostate gland is not completely ablated, and the remaining prostate epithelium continues to produce PSA.
• In high-risk patients, external beam radiotherapy has also been combined with brachytherapy. The brachytherapy is usually given first, so that the external beam therapy can be discontinued if the patient begins to experience toxicity.

Brachytherapy

• Radioactive sources (seeds or needles) are implanted directly into the prostate gland, and sometimes into the surrounding tissues, to deliver a high dose of radiation to the tumor while sparing, to the extent possible, the bladder and the rectum.
• The most commonly used permanent implants are iodine-125 or palladium-103 seeds.
• Ultrasound-guided transperineal brachytherapy has become an accepted modality for the treatment of localized prostate cancer using 1251 or 103 Pd radiation sources. The radiation doses delivered to the prostate are approximately 145 Gy for iodine and 125 Gy for palladium.  
• Optimal candidates have a serum PSA of less than 10 ng/mL, and a Gleason score of 6 or lower. Many centers utilize short-term neoadjuvant hormonal blockade given the difficulty in treating prostate glands larger than 50 g. Conversely, glands smaller than 20 g are difficult to implant. 
• Urinary retention occurs in up to 22% of patients.
• Short-term complications include urinary retention, urethritis, and irritative voiding symptoms, especially in patients with a history of lower urinary tract obstructive symptoms. Long-term major complications include stricture or contracture development and proctitis. Incontinence is uncommon but averages 20 percent in men with a history of transurethral resection of the prostate. 

Stereotactic Radiotherapy (“Cyberknife”)

• More data is needed to include in this section 

Adjuvant Radiotherapy after Radical Prostatectomy

• Retrospective cohort studies have shown that postoperative radiotherapy reduces recurrence rates in patients with pathologic stage T3 disease and positive margins. 
• A trial of adjuvant radiation after radical prostatectomy of men with stage pT3 prostate cancer or positive margins revealed that adjuvant radiation reduced the recurrence rate and that positive margins were the strongest predictor of benefit.  
• Side effects of adjuvant radiotherapy also include a 5% to 10% risk of radiation proctitis and a 50% probability that return of erectile function will be materially compromised.
• It is impossible to compare the results of surgery with those of radiotherapy because of the difference in the end points used for treatment failure, that is, undetectable PSA for surgery versus the ASTRO or Phoenix criteria for radiotherapy.

Primary Hormone Therapy

• Primary androgen-deprivation therapy may be appropriate for older men, those with significant medical comorbidities precluding the use of curative therapy, and those who do not wish to undergo curative therapy.
• Cardiovascular evaluation is recommended prior to treatment of men at risk for cardiovascular complications.
• Hormone therapy is never curative; nevertheless, many patients experience long-term remissions. Luteinizing hormone–releasing hormone analogs are commonly used. 
• Antiandrogens produce less sexual dysfunction and osteoporosis but have a greater risk for adverse cardiovascular complications.

Cryosurgery

• Current technology uses argon gas circulating through hollow needles to freeze the prostate and helium gas to warm the urethra. 
• Cryoablation has been used as primary treatment for salvage after radical prostatectomy or radiotherapy. 
• A prior transurethral resection of the prostate is considered a relative contraindication to cryoablation.
• An undetectable PSA level is seldom attainable after cryoablation.Pelvic pain persists.
• Complications associated with salvage cryoablation were much more frequent than for primary treatment.
• Complications of salvage cryotherapy included 4.4% incontinence, 1.2% rectal fistula, and 3.2% requiring a transurethral resection of the prostate for obstruction.

High-Intensity Focused Ultrasound (HIFU)

• Transrectally applied high-intensity focused ultrasound (HIFU) can elevate the tissue temperature of the prostate up to 100° C.
• Treatment is performed under general or spinal anesthesia and takes 1 to 4 hours, depending on the prostate volume, which should not exceed 40 cc.
• Most patients require a urethral or suprapubic catheter for several days.
• The procedure is usually well tolerated; the most common side effect is acute urinary retention, occurring in about 20% of patients. 
• Other potential complications are urinary fistula, incontinence, urethral stricture, and perineal pain. 
• Erectile dysfunction has been reported in 27% to 61%.
• Clinical trials are continuing in the USA and other countries.  

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