Prostate Cancer


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Prostate cancer is the most common noncutaneous cancer that occurs in a man's prostate. The prostate gland is a chestnut-shaped reproductive organ which adds secretions to the sperm. Although prostate cancer can be a slow-growing cancer, it is the second most common cause of cancer death in males.

The prostate lies below the bladder and encompasses the prostatic urethra. It is surrounded by a capsule and is separated from the rectum by a layer of fascia termed the Denonvilliers aponeurosis. The inferior vesical artery, which is derived from the internal iliac artery, supplies blood to the base of the bladder and prostate. The capsular branches of the inferior vesical artery help identify the pelvic plexus arising from the S2-4 and T10-12 nerve roots. The neurovascular bundle lies on either side of the prostate on the rectum. It is derived from the pelvic plexus and is important for erectile function.

Local spread and metastasis
When these cancers are locally invasive, the transitional-zone tumors spread to the bladder neck, while the peripheral-zone tumors extend into the ejaculatory ducts and seminal vesicles. Penetration through the prostatic capsule and along the perineural or vascular spaces occurs relatively late. Prostate cancer can metastasize to other parts of the body spreading to bone and lymph nodes. The lower-grade tumors have a slow growth while high-grade lesions progress to metastatic disease spreading rapidly.

Prostate cancer may not show any signs or symptoms in its early stages. In such cases, diagnosis is based on abnormalities found while screening for prostate-specific antigen (PSA) level or findings on digital rectal examination (DRE). Prostate cancer can also be identified when tissue is removed during transurethral resection to manage obstructive symptoms from benign prostatic hyperplasia.

Localized prostate cancer can be treated with radical prostatectomy, cryotherapy, radiation therapy, or active surveillance, also termed watchful waiting. Metastatic prostate cancer is not curable. The cancer can be managed by therapy directed at relief of particular symptoms (eg, palliation of pain) or attempts to slow further progression of disease. Surgical treatment currently includes nerve-sparing techniques, laparoscopic procedures, robotic-assisted procedures, and variations on the classic retropubic prostatectomy. Multiple forms of radiotherapy are now available. These include conventional radiotherapy, 3-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and brachytherapy.
Symptoms of Local Disease
Before the advent of PSA testing, patients with prostate cancer commonly presented with local symptoms. Urinary retention developed in 20-25% of these patients, back or leg pain developed in 20-40%, and hematuria developed in 10-15%. With PSA screening, typical symptoms and their frequency include:
  • Urinary frequency (38%)
  • Decreased urine stream (23%)
  • Urinary urgency (10%)
  • Hematuria (1.4%)
However, these symptoms are not specific to prostate cancer. They can arise from various other ailments.

Symptoms of Advanced Disease
Advanced prostate cancer may result from any combination of lymphatic, hematogenous, or contiguous local spread. The cancer extends beyond the prostate capsule and into the seminal vesicles or beyond. Skeletal symptoms are also common as prostate cancer has a strong tendency of metastasizing to bone. Uremic symptoms due to ureteral obstruction can also be caused by local prostate growth or retroperitoneal adenopathy secondary to nodal metastasis.

Symptoms of metastatic and advanced prostate cancer may include:
  • Anemia
  • Loss of weight and loss of appetite
  • Bone marrow suppression
  • Bone pain, with or without pathologic fracture
  • Spinal cord compression
  • Lower extremity pain and edema due to obstruction of venous and lymphatic tributaries by nodal metastasis

The initial investigation for prostate cancer involves serum prostate-specific antigen (PSA) testing, digital rectal examination (DRE) and prostate biopsy. Further investigation depends on the clinical staging. The clinical stage helps the doctor to find out how far the cancer has spread. Higher clinical stages of cancer depict increased risk of extraprostatic spread which means the cancer is no longer confined to the prostate. Gleason score helps the doctor to determine the stage of prostate cancer. It requires accurate assessment during biopsy. DRE findings, PSA level, and Gleason score are the key factors in staging workup and predicting patient prognosis.

Men with PSA levels less than 10 ng/mL and low- or moderate-grade histology (Gleason score ≤ 7) with no or minimal abnormal findings on physical examination may proceed to surgery or brachytherapy without further studies. Men with PSA levels greater than 10 ng/mL, high-grade histology (Gleason score >7), or physical findings that suggest stage T3 disease should probably undergo imaging studies.

Preoperative workup includes the following:

  • Chest radiography
  • Complete blood count
  • Basic metabolic panel
  • Prothrombin time and activated partial thromboplastin time
  • Electrocardiography

Diagnosis of prostate cancer involves:

Physical Examination
Digital rectal examination (DRE) is done to check for any abnormalities of the prostate that might be helpful in the early diagnosis of prostate cancer. Diagnosis is examiner-dependent, and serial examinations over time are best. However, physical examination findings alone cannot reliably differentiate a cyst or calculus from a tumor; therefore, a biopsy needs to be performed in these circumstances.

An irregular firm prostate or nodule may suggest cancer; however, prostate that feel normal may also be cancerous. It is very important to pay careful attention to the prostate consistency, along with the seminal vesicles and adjacent organs, in order to detect the spread of the disease to these structures. Obliteration of the lateral sulcus or seminal vesical involvement often indicates locally advanced disease. Neurological examination, including determination of external anal sphincter tone, should be performed to help detect possible spinal cord compression. However, findings such as paresthesias or wasting are uncommon. Findings in patients with advanced prostate cancer may include:

  • Cancer cachexia
  • Bony tenderness
  • Lower extremity lymphedema or deep venous thrombosis
  • Adenopathy
  • Overdistended bladder due to outlet obstruction

Prostate-specific antigen (PSA)
The upper limit of normal for PSA is 4 ng/mL. With a PSA level of 4-10 ng/mL, the likelihood of prostate cancer is about 25%; with a level above 10 ng/mL, the likelihood is over 50%.

Some advocate age-related PSA cutoffs, such as 2.5 ng/mL for the fifth decade of life, 3.5 ng/mL for the sixth decade of life, and 4.5 ng/mL for the seventh decade of life.

To improve the accuracy of PSA for detecting prostate cancer, a variety of approaches have been proposed. These include the velocity of PSA level increase and the percentage of free PSA.

Digital rectal examination

DRE can be done to check for any abnormalities in the prostate in men. This test helps the doctor to determine the texture, shape and size of the gland.

Various factors are considered before a DRE is performed. A nodule can be an important finding, but other factors such as asymmetry, difference in texture, and bogginess are important clues and should be considered in conjunction with the PSA level. Change in texture over time can also offer important clues about the need for intervention.

DRE findings alone cannot be considered to diagnose a cancer. Presence of cysts or stones cannot be accurately differentiated from cancer. DRE forms the basis of clinical staging of the primary tumor (ie, tumor [T] stage in the tumor-node-metastases [TNM] staging system), in case a cancer is detected. In current practice, most patients diagnosed with prostate cancer have normal DRE results but abnormal PSA readings.

Prostate Biopsy
Patients may need to undergo prostate biopsy if:

  • High PSA level is detected
  • DRE findings are abnormal

In this, a small sample of tissue is taken from the prostate and examined under microscope to check for cancer cells. Transrectal ultrasonography (TRUS) is used to guide the biopsy. TRUS also permits measurement of the volume of the prostate. Hypoechoic areas on TRUS are commonly associated with cancers. However, this finding is not specific enough for diagnostic purposes.

The number of biopsy samples that should be taken is debated. The former standard consisted of 6 samples taken in a sextant pattern. In extended-pattern biopsies, the sextant samples are supplemented with 2 lateral samples from each lobe for a 10-biopsy scheme, or 6 lateral peripheral zone samples for a 12-biopsy scheme; 18-core biopsy protocols are also used, especially for larger glands. In addition, samples may be taken from palpable nodules or ultrasonographically suspicious areas.

Imaging Studies

  • CT and MRI
  • CT scan is an imaging modality with evidence-based guidelines. Neither CT scanning nor MRI can be used to determine whether lymph nodes are reactive or contain malignant deposits unless the nodes are significantly enlarged and a percutaneous biopsy can be performed. Conventional endorectal MRI is helpful for localizing cancer within the prostate and seminal vesicles and for local staging.
  • Bone scan
  • Bone scan is not necessary in patients who do not show any skeletal symptoms and a serum PSA level of 10 ng/mL or less, as suggested by American College of Radiology (ACR). However, in case of specific circumstances such as T3 or T4 disease or a high Gleason score (>6), exceptions can occur. In comparison, the EAU guideline recommends a bone scan only if the PSA is greater than 20 ng/mL. A bone scan may be performed as a baseline for treatment response in patients with recurrent metastatic disease at high risk of having bony metastatic disease. Activity in the bone scan may not be observed until 5 years after micrometastasis has occurred; therefore, negative bone scan results do not rule out metastasis. In biochemical failure, a follow-up bone scan usually has no value until the PSA level exceeds 30 ng/mL.
  • Chest radiography
  • Chest radiography can be used as a baseline study. It may also help reveal rare pulmonary metastases in select cases.
  • Blood Studies
  • Blood studies should include a complete blood count and a chemistry profile, including serum creatinine, liver function tests, and acid and alkaline phosphatase. Any abnormal results on these tests may warrant additional studies.
  • Urinalysis
  • Urinalysis should be performed. If results are abnormal, ie, indicating the presence of an infection, urinalysis should be followed by a urine culture, especially if the patient is symptomatic.

Localized Prostate Cancer
In localized prostate cancer the cancer has not spread beyond the prostate. The treatment involves prostatectomy, cryotherapy, radiation therapy, or active surveillance. Radiation therapy along with androgen ablation can also be recommended as a treatment procedure. However, radical prostatectomy may be appropriate as an alternative to radiation therapy in some cases.

There is no consent regarding the best treatment available for localized prostate cancer. The treatment decision can be based on the progression of the cancer.

For low risk localized prostate cancer treatment may involve active surveillance or watchful waiting. In patients with intermediate-risk localized prostate cancer, appropriate treatment options include active surveillance, interstitial prostate brachytherapy, external beam radiotherapy, and radical prostatectomy.

Treatment should be based in part on the patient’s preferences and functional status. A patient who chooses conventional dose external beam radiotherapy may prolong survival by the use of hormonal therapy for 6 months. The patient should be informed about the benefits and drawbacks of the most commonly accepted interventions for localized prostate cancer that includes active surveillance, radiotherapy, and radical prostatectomy.

Active surveillance
Also termed as watchful waiting, involves regular examination to monitor symptoms of prostate cancer. It is recommended for elderly patients and patients with life-limiting comorbidities and a life expectancy of less than 10 years. Elderly patients with relatively short life expectancy, a slow growing prostate cancer will not cause death. In such cases, watchful waiting is the best treatment possible. If the cancer progresses treatment may include radical prostatectomy.

For patients with longer life expectancy, active surveillance is sometimes considered in patients with T1-2a disease, a Gleason score of 2-6, and a PSA level below 10 ng/mL. In addition, watchful waiting is appropriate in patients who do not harbor well-differentiated tumors.

Patients under active surveillance typically undergo prostate-specific antigen (PSA) testing every 3 months and repeat biopsy at 18- to 24-month intervals. Biopsy findings are the most important factor in deciding whether to pursue treatment.

Radical prostatectomy
Radical prostatectomy involves removal of the prostate and seminal vesicles. Currently, the procedures used to remove the prostate gland include radical retropubic prostatectomy and radical perineal prostatectomy. Radical retropubic prostatectomy be performed using either an open or laparoscopic technique. The laparoscopic technique can be performed with robotic assistance.

Though specific criteria are suggested for proceeding with radical prostatectomy, the treatment choices should be individualized to each patient’s specific situation. The general criteria are:

  • Patient age younger than 75 years
  • Few comorbidities, with life expectancy longer than 10 years
  • Gleason score of 7 or less
  • PSA level less than 20 ng/mL
  • Complications from radical prostatectomy may widely vary depending on the surgeon and center. High-volume centers generally have superior outcomes. The complications may include impotence, urinary incontinence, strictures, and, possibly, fecal incontinence.

Radiation therapy
Radiation therapy may be delivered in the form of external beam radiation therapy (now termed intensity modulated radiation therapy [IMRT]) or brachytherapy (ie, the insertion of radioactive seeds into the prostate gland). In general, after 2 years, the quality of life profile between IMRT and surgery is similar. Radiation therapy does have a slightly increased risk of persistent fecal urgency and incontinence of gas.

Non–Organ-Confined Disease
When imaging studies provide clear evidence of non–organ-confined disease (eg, seminal vesicle or periprostatic involvement), the treatments offered may vary. Management of locally advanced prostate cancer (T3-4N0M0) is often with external beam radiotherapy. If brachytherapy is used, it is often combined with external beam and hormone therapy. Because of the aggressive nature of these tumors, watchful waiting is an option only in highly selected patients with life expectancies of less than 5 years.

Management of Advanced and Metastatic Disease
For symptomatic metastatic prostate cancer, androgen deprivation therapy is considered the primary approach of treatment. However, androgen deprivation therapy has been found to be palliative, not curative. In metastatic disease, this therapy has yielded a median progression-free survival of 18-20 months and an overall survival of 24-36 months.

Although androgen deprivation therapy is associated with significant responses, its curative potential is limited because of the inherent heterogeneity of prostate cancer and the inability of hormones to eradicate all prostate cancer clones, both the androgen-dependent and androgen-independent components. Most patients progress to castrate-resistant prostate cancer, also termed androgen-independent cancer. These patients have disease progression despite castration levels of androgens.

Combined androgen blockade
Combined androgen blockade recognizes the 10% contribution of adrenal androgens to the total body testosterone. Labrie and colleagues described the concept of combined androgen blockade, in which LHRH accomplished medical castration and antiandrogens achieved peripheral blockade.

Radiation therapy
In patients with metastatic prostate cancer, radiation is also applied for palliative purposes. It is used in patients with castrate-resistant disease with painful bone metastases and in patients with impending spinal cord compression.

Surgical management of advanced and metastatic disease
Bilateral orchiectomy was previously used to produce androgen deprivation in patients with widely advanced and metastatic prostate. Since the introduction of LHRH agonist therapy, surgical intervention has been practiced less often. An indication for immediate bilateral orchiectomy is spinal cord compression.Surgical intervention is mandatory for pathologic fracture of weight-bearing bones.

Biochemical Failure or Recurrence
The most common presentation of advanced prostate cancer is a patient with a rising PSA level in whom initial local therapy has failed. Generally, after a radical prostatectomy, the PSA level should be less than 0.2 ng/mL and, after radiation therapy, less than 0.5 ng/mL. The definition of a rising PSA level is not consistent in the literature, but many agree that 2 consecutive PSA level elevations is considered biochemical failure. Other important prognostic indicators include PSA velocity, time to PSA nadir, time to PSA recurrence, and pattern of PSA recurrence.

Therapeutic options include the following:

  • LHRH agonists - Offered in 1-month, 3-month, and once-yearly depots
  • Complete androgen blockade - LHRH agonist with an oral antiandrogen
  • Nonsteroidal antiandrogen monotherapy
  • Gonadotropin-releasing hormone (GnRH) agonist

Management of castrate-resistant prostate cancer
In patients with castrate serum testosterone levels, castrate-resistant prostate cancer is defined as 2-3 consecutive rises in PSA levels obtained at intervals of greater than 2 weeks and/or documented disease progression based on findings from CT scan and/or bone scan, bone pain, or obstructive voiding symptoms. In a subgroup of patients, the PSA level does not rise at diagnosis or throughout the entire course of the disease.

If given enough time, all patients with metastatic disease become resistant to androgen ablation. The median time to symptomatic progression after a rise in PSA level of more than 4 ng/mL is approximately 6-8 months, with a median time to death of 12-18 months.

Therapeutic options for patients with castrate-resistant prostate cancer are limited, with lack of evidence for long-term survival. The best outcome for these patients is to maintain or to improve their quality of life.
Short-term palliative response and improved quality of life in these patients is achieved presently by single or multimodal therapies, which may include the following:

  • Second-line hormonal manipulations
  • Megestrol
  • Addition of antiandrogens
  • Corticosteroids
  • Ketoconazole
  • Radiation therapy
  • Chemotherapeutic agents (eg, mitoxantrone, estramustine, taxanes)
  • Bisphosphonates/RANK ligand
  • Suramin
  • Chemohormonal therapy
  • Other investigational approaches

Bisphosphonates, which are stable analogs of calcium pyrophosphate, inhibit osteoclastic activity in bone, relieving bone pain. They may also limit progression of prostate cancer. Bisphosphonates used in conjunction with antiangiogenic factors may increase the risk of osteonecrosis of the jaw over bisphosphonates alone. This may warrant pretreatment evaluation of dentition.

RANK ligand binders (denosumab) stop the initiation of the vicious bone cycle by preventing the activation of osteoblast/osteoclast activity. These are given as a monthly subcutaneous injection, as opposed to an infusion.

Docetaxel (Taxotere) is the drug of choice over mitoxantrone in patients with advanced prostate cancer that has become hormone refractory. The US Food and Drug Administration (FDA) has approved docetaxel for use in combination with prednisone for this purpose.

Mitoxantrone is also approved for use in combination with prednisone or hydrocortisone. It has been shown to induce statistically significant response in controlling pain and improving quality of life, time to treatment failure, and time to disease progression compared with glucocorticoids alone.

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