Clinical Condition

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Prostate Cancer / General Information

The prostate is the walnut shaped gland in males located between the bladder and the urethra that is involved in the liquefaction of the male ejaculate. The gland is made up of secretory cells with a surrounding connective tissue stroma. Prostate cancer is the transformation of these secretory cells into malignant cells that have the potential to grow more rapidly and spread outside of the prostate. Prostate cancer will often start out localized in the prostate, but can then spread into adjacent tissue structures and lymph nodes if not detected early. The most common site of metastatic disease is the bone, but it can also spread to the lung, liver and other organs.

FIRST & FOREMOST

Prostate cancer is the most common non-skin malignancy in men and is responsible for more deaths than any other cancer, except for lung cancer. However, microscopic cancer is found at autopsy in many if not most men. PSA (a blood test) has allowed early identification and treatment of prostate cancer. Although nearly a decade since the PSA blood test has been introduced, absolute proof that PSA saves lives has not been scientifically proven. However, the death rate from prostate cancer is now decreasing in the United States, suggesting a medical benefit of PSA use. In addition, refinements to radiation and surgical techniques allow more effective treatment with fewer side effects. More information is provided throughout this section, with a recent published literature update in the “What’s New” section.

Prostate Cancer / Causes & Risk Factors

CAUSES

Prostate cancer is the most commonly diagnosed cancer in men and the second leading cause of cancer deaths in men after lung cancer. It is estimated to be found in as many as half of all men over the age of 70 and in almost all men over the age of ninety. Since the discovery of the blood test for Prostate Specific Antigen (PSA) in the 1980’s, prostate cancer can now be detected at a much earlier stage.

In 1999, there were over 250,000 new cases of prostate cancer with 45,000 deaths. The average age of diagnosis is 72 years and 95% of cases are diagnosed between the ages of 45-89.

The incidence of prostate cancer varies among different ethnicities. The incidence is highest in African Americans and lowest in Asian Americans. Mortality from prostate cancer has slowly risen over the last 10 years which is likely attributable to the fact that the American population is aging and experiencing less cardiovascular mortality.

RISK FACTORS

It is largely unknown as to what causes prostate cancer. It is thought, as with other malignancies, to be a combination of environmental risk factors in conjunction with a genetic predisposition. It is important to understand that risk factors are not “causes”, but are factors that make you statistically more likely than others in the general population to have a certain condition. The following is a list of some of the more well known and accepted risk factors for the development of prostate cancer.

Risk Factors:

  1. Age
  2. Family History
  3. Race
  4. Dietary Fat
  5. Hormones
  6. Cadmium
  7. Vitamin A & D

Advanced age, family history and race are the three most important factors. It is for this reason that men begin screening for prostate cancer at the age of 50, unless they are African American or have a family history, then screening is to begin at the age of 40. (See section on Prevention and Screening) Approximately 9% of all prostate cancers are termed “familial.” This is a form of cancer that is genetically passed on in an autosomal dominant fashion. This tends to cause prostate cancer in younger individuals (less than age 55). Furthermore, prostate cancer is unique in that it exists in two forms. There is a latent form that, although detectable, will not likely metastasize and there is a clinically evident form which is seen in approximately 1 out of 6 American men and has a potentially lethal course

Prostate Cancer / Symptoms

Localized prostate cancer does not cause any symptoms. Until the development of the PSA blood test, detection of localized prostate cancer could only occur if the cancer grew to the point where it was able to be felt on digital rectal examination or if it was found incidentally during transurethral resection of the prostate for presumed benign enlargement.

Prostate cancer that has metastasized may cause pain, especially from spread to the bones. Weakness from anemia may occur if prostate cancer has affected multiple areas of the bone marrow, limiting the body’s ability to produce red blood cells. In advanced cases, enlargement of lymph nodes in the pelvis can obstruct urine flow, resulting in backup of urine in the kidneys (hydronephrosis) with possible kidney failure if this process affects both kidneys.

Locally advanced prostate cancers may obstruct urinary flow and/or cause severe irritation in the bladder region when the cancer extends from the prostate into the base of the bladder. Treatment of this locally advanced cancer can be very difficult. Obstruction to urinary flow may be opened by transurethral resection of the prostate, but there is a delicate balance between opening the urethra adequately to void and opening the urine passage too much, resulting in incontinence. Fortunately, there appear to be fewer men presenting with locally advanced cancers, possibly because of the more active and frequent application of local treatments with earlier detection of prostate cancer. This change in detection occured primarily in the late 1980s and early 1990s with widespread application of the PSA blood test.

Prostate Cancer / Evaluation
Presentation/Screening/Diagnosis of Prostate Cancer

Prostate cancer is most often diagnosed by an asymptommatic elevation of one’s PSA value as found on a blood test during a routine physical examination. Prostate cancer rarely causes symptoms at its early stages.

Prostate cancer is most often diagnosed by an asymptommatic elevation of one’s PSA value as found on a blood test during a routine physical examination. Prostate cancer rarely causes symptoms at its early stages. The majority of prostate cancers arise in the peripheral (outer) portion of the gland. As a result, a nodule that is palpated on rectal examination should warrant further evaluation with a biopsy to rule out cancer. A decrease in urinary stream, hesitancy and frequent urination are all symptoms that most often correspond to an enlarged prostate that occurs with aging. In its advanced stages, prostate cancer can also be responsible for these symptoms. The digital rectal examination (DRE) along with the blood test for PSA are the main modalities utilized to detect prostate cancer. If either the PSA value is elevated or a prostate nodule is noted on DRE, then a trans-rectal ultrasound guided (TRUS) biopsy of the prostate is performed.

DIGITAL RECTAL EXAMINATION (DRE)

A rectal examination is an integral part of any complete physical examination. Duriing the rectal examination the prostate can be examined and palpated for any nodularity. The physician is actually feeling the peripheral portion of the prostate where most cancers arise. A palpable nodule, regardless of one’s PSA value, should warrant a biopsy. Although only 20-50% of these nodules will reveal cancer, a biopsy should still be undertaken. In addition, approximately 25% of men with prostate cancer will actually have a normal PSA value, lending more importance to the digital rectal examination.

PROSTATE-SPECIFIC ANTIGEN (PSA)

PSA is a protein produced by the prostate and periurethral glands in the male. It is involved physiologically in helping liquefy the semen prior to ejaculation. PSA circulates in the blood in both the bound and unbound forms. In the bound form, the PSA molecule is bound to protein called alpha-1-antichymotrypsin (ACT) to form a PSA-ACT complex which is detectable on blood immunoassays. The “free” or unbound form of PSA is the “inactive” form of PSA and is also detectable on blood tests. The free plus the bound form are equal to the total PSA value. Most blood tests report on the bound form of PSA. The unbound or “free” PSA has more recently been used to increase the specificity of the PSA test in detecting prostate cancer. The half life of the PSA molecule is 2-3 days and thus after ones of 0-4 is considered “normal.” This, however, has changed over the last few years. The concept of age-specific PSA has been introduced. Age specific normal are listed below.

  • Age 40-50: 0-2.5ng/ml
  • Age 50-60: 0-3.5ng/ml
  • Age 60-70: 0-4.5ng/ml
  • Age 70-80: 0-5.5ng/ml

The PSA value increases with age mostly as a result of the growth in size of the prostate with age. Although somewhat controversial, the concept of the age-specific PSA evolved as an attempt to increase earlier detection in young men who will benefit from the treatment while at the same time decrease unnecessary biopsies in older men. Other concepts that have emerged in an attempt to improve the PSA test are listed below:

  • PSA velocity – the rate of change of PSA over time. An increase in PSA of 0.75ng/ml or above over a year should initiate a prostate biopsy.
  • PSA density(PSAD) – PSA value divided by the size of the prostate. A PSAD of 0.15 or above should initiate a biopsy.
TRANS-RECTAL ULTRASOUND GUIDED BIOPSY (TRUS)

TRUS biopsy of the prostate utilizes an ultrasound probe that is passed into the rectum that uses sound waves to visualize the prostate on a monitor. Through direct visualization of the prostate, a special biopsy needle can be safely and accurately introduced into the prostate to perform both random biopsies and directed biopsies of nodules. Usually, sextant biopsies are taken of the prostate and a total of six cores are obtained for pathological examination. Oral antibiotics are administered before and after the procedure and patients are sent home the same day. The entire biopsy lasts approximately 15 minutes. Patients may notice some blood in their urine after the biopsy which should resolve within a few days

Pathology of Prostate Cancer: What will your prostate biopsy reveal?

Many prostate biopsies that are negative for carcinoma may reveal some degree of inflammation of the prostate know as prostatitis. This is of no true clinical significance and is very common in the aging male population.

PROSTATITIS

Many prostate biopsies that are negative for carcinoma may reveal some degree of inflammation of the prostate know as prostatitis. This is of no true clinical significance and is very common in the aging male population.

PROSTATIC INTRA-EPITHELIAL NEOPLASIA (PIN)

High-grade prostatic intraepithelial neoplasia is a clinically significant finding on prostate biopsies that is associated with a presence of invasive carcinoma. Prostatic intraepithelial neoplasia (PIN) consists of architecturally benign prostatic ducts lined with cytologically atypical cells. Low grade PIN, previously referred to as mild dysplasia or PIN-1, is of no prognostic significance. Patients with low grade PIN are at no greater risk of having an invasive carcinoma found on repeat biopsy. When high-grade PIN is found on needle biopsy, there is a 30 to 50 percent risk of finding carcinoma on subsequent biopsies (Keetch et al., 1995). By itself, PIN does not give rise to elevated serum PSA levels. However, the finding of high-grade PIN without invasive carcinoma on needle biopsy, should result in subsequent additional prostatic biopsies. Biopsies should be performed both in the region where PIN was seen as well as other areas of the prostate, in the typical sextant pattern. Although high grade PIN appears to be a precursor lesion to many peripheral intermediate grade and high grade adenocarcinomas, PIN is not a required precursor for carcinomas to arise within the prostate (Epstein, 1996).

ADENOCARCINOMA OF THE PROSTATE

Almost all cancers of the prostate are adenocarcinomas. They tend to arise from the peripheral (outer) zone of the prostate in 85 percent of cases. Adenocarcinoma of the prostate occurs in more than one site (multifocal) in more than 85 percent of cases. Even if it appears to be one-sided (unilateral) on rectal examination, these lesions occur on both sides (bilateral) in approximately 70 percent of surgical specimens that are examined pathologically. Although prostatic adenocarcinoma can be found in up to 50 percent of men in autopsy series, these lesions are small, low-grade, and clinically insignificant. These tumors are very rarely detected during clinical screening with PSA blood tests, rectal examination, and transrectal ultrasound-guided biopsy of the prostate (Walsh, 1994).

Adenocarcinomas of the prostate are graded by the pathologist according to their degree of differentiation and overall aggresiveness. They are given a Gleason Score which is a number from 2-10. Numerous grading systems have existed for evaluation and diagnosis of prostate cancer. By far, the Gleason grading system is clearly the most widely accepted. The Gleason system of prostate cancer grading is based on the glandular and cellular pattern of the tumor as evaluated at relatively low magnification. The Gleason grading system combines the two most common (primary and secondary) architectural patterns of cancer within the sampled specimen. Each of the two most common patterns is assigned a grade from one to five, with one the most differentiated and least aggressive and five the least differentiated or most aggressive pattern. The value of the Gleason grading system is its ability to predict survival rates. Importantly, Gleason grading may provide prognostic information that is to some degree independent of the extent of local tumor. Gleason sum score is reported as the two scores added together. For example, if the most common pattern of grading was a 3 pattern and the second most common pattern was a 4, the Gleason grade would be reported as Gleason 3+4=7 (Epstein et al., 1996).

OTHER CARCINOMAS OF THE PROSTATE

Aside from adenocarcinoma of the prostate, a biopsy of the prostate could also reveal other types of cancer. For example, mucinous adenocarcinoma are a subtype of tumor that have a very aggressive biologic behavior and tend to metatstasize early in their course. Small cell carcinoma is another type of prostate cancer formed from the hormone producing (neuroendocrine) cells of the prostate. These tend to form in men treated with long term hormonal ablation therapy but can also form on their own. Finally, transitional cell carcinoma can form in the prostate. This typically a cancer that forms in the bladder, but can also form in the portion of the bladder that lines the prostate (urothelium).

Prostate Cancer / Staging & Progression
STAGING

There are several staging systems to categorize the levels of prostate cancer. The most widely accepted system is the TNM classification.

Stage I – (T1) – Tumor remains confined to the prostate and is too small to be detected on DRE. This is an incidentally found cancer either by an elevated PSA or found after a transurethral resection of the prostate.
Stage II – (T2) – Tumor is still confined to the prostate, but is now large enough to be felt on DRE.
Stage III – (T3) – The prostate cancer has spread through the prostatic capsule and may involve locally surrounding tissues such as the seminal vesicles.
Stage IV – (T4) – Metastatic prostate cancer in which the cancer involves lymph nodes or bony sites or other organs such as the liver or lungs.
NATURAL PROGRESSION

Prostate cancer tends to be a slowly progressive cancer. Absolute prediction of when a localized cancer will spread and cause significant problems is not well understood. Some information has been provided by a study published in JAMA (The Journal of the American Medical Association). In this study of patients diagnosed with prostate cancer in Conneticut who did not have initial treatment, the histologic analysis (Gleason’s sum score) was the most accurate apparent predictor of the speed of prostate cancer progression. Men with low grade prostate cancers (Gleason sum score 2 to 4) had such a low rate of progression that survival over 15 years was very similar to that of age-matched men who did not have cancer. However, men with Gleason 8-10 cancers had only a 50% survival rate at 5 years. Intermediate progression and death rates occurred for men with Gleason 5-7 sum scores.

Progression after biochemical (PSA-detected) recurrence following attempted local treatment can also be predicted based on the time of PSA detection after treatment and the rate of PSA change. Recent information has suggested that men with prostate cancer who recur with a PSA level above 0.3 ng/ml after radical prostatectomy are likely to do very well for a long period of time if the recurrence is first detected after 2 years and the PSA doubling time (the time necessary for PSA level to increase by a factor of 2) is greater than 10 months. Men with these characteristics will typically not develop any evidence of prostate cancer spread to bone for at least 8 years after detection of the PSA increase (Pound et al., JAMA.)

Prostate Cancer / Treatment Options

Cryosurgery

This is a relatively new modality for the treatment of prostate cancer. It involves placing several percutaneous probes into the prostate and the prostate is then frozen, thawed and then frozen again.

This is a relatively new modality for the treatment of prostate cancer. It involves placing several percutaneous probes into the prostate and the prostate is then frozen, thawed and then frozen again. This freezing technique causes the death of cancer cells. Since it is relatively new, there is no long term data concerning is efficacy.Robotic Prostatectomy

This is a relatively new modality for the treatment of prostate cancer. It involves using a surgical robot to remove the cancer with minimal discomfort and blood loss.

Continue discovery >

Hormonal Ablation Therapy

Prostate cancer grows in response to testosterone. Testosterone is produced in the testicles and the adrenal gland. Testosterone production can be stopped in two ways.

Prostate cancer grows in response to testosterone. Testosterone is produced in the testicles and the adrenal gland. Testosterone production can be stopped in two ways. The testicles can be removed with a procedure called an orchiectomy. Similarly, testosterone production can be stopped with medications such as leuprolide or goserelin acetate that suppress the pituitary gland and thus decrease production in the testes. This is know as androgen deprivation therapy (ADT). ADT is not a curative therapy, but is reserved for metastatic disease or for patients that will not medically tolerate surgery or radiation. ADT can relieve symptoms from painful bone metastases and slow the overall growth rate of prostate cancer cells. Other medications used for ADT are listed below:

  • Aminoglutethamide
  • Casodex (biclutamide)
  • Cyproterone
  • DES (diethylstilbesterol)
  • Estrogen (megestrol acetate)
  • Eulexin (flutamide)
  • Lutenizing Hormone Releasing Hormone (LHRH,leuprolide/ Zoladex-goserelin)
  • Nizoral (ketoconazole)
Management of Prostate Cancer

Prostate cancer may be divided, based on its clinical presentation into localized or advanced disease. For men with clinical T1-T2 prostate cancer, curative therapy or observation are options.

Prostate cancer may be divided, based on its clinical presentation into localized or advanced disease. For men with clinical T1-T2 prostate cancer, curative therapy or observation are options. For men with advanced disease (T3 or above), hormonal therapy and other palliative treatments are the primary approaches for consideration. Men who have a less than 10 year life expectancy with localized disease, as well as men with less than 5 year life expectancy and asymptomatic advanced disease, expectant management is the optimal initial treatment. Management of localized prostate cancer is a controversial issue, in part because the natural history of localized prostate cancer has been only segmentally elucidated. At present, prostate cancer is the most common cancer diagnosed in men in the United States and the second most common cause of cancer death. The ratio of death rate to incidence suggests that between 20 and 50 percent of men with a clinical diagnosis of prostate cancer will die of the disease. In considering the management of localized prostate cancer, it is important to remember that men with latent, incidental microscopic tumors can only rarely have these cancers detected using today’s screening tests of PSA and transrectal ultrasound-guided biopsies (Gardner et al., 1998). Preliminary studies that have evaluated a program of observation or watchful waiting rather than screening with a PSA-based approach suggest that the death rate from prostate cancer will decrease with screening. In addition, the small decrease in prostate cancer death rates associated with the increased screening by PSA (with a five- to seven-year lag period) suggests that earlier screening, detection and treatment of men with prostate cancer may have resulted in saving lives. However, little evidence is available at this point with well-performed randomized studies to confirm that treatment of localized prostate cancer will actually decrease death rates from this disease. In distinction, there is widespread acceptance that breast cancer is an important cause of death in women (Walsh, 1994).

Studies on the natural history of localized prostate cancer have suffered from selection biases, but they allow us some insight into what would occur if patients were not treated with curative intention for localized disease. Almost all of these studies indicate that men with metastatic disease had unrecognized advanced disease at least ten years prior to diagnosis. This is supported by the studies of Carter et al. (1992) where serum PSA levels were followed serially in a number of patients in the Baltimore Longitudinal Study of Aging. Therefore, patients who are candidates for curative local therapy should have a 10-year life expectancy.

Metastatic Prostate Cancer and Chemotherapy

For patients who have hormone-resistant prostate cancer growth, several options including investigational treatments are available. Most patients who are treated with hormone-resistant prostate cancer have symptomatic disease.

MANAGEMENT OF ADVANCED PROSTATE CANCER

For patients who have hormone-resistant prostate cancer growth, several options including investigational treatments are available. Most patients who are treated with hormone-resistant prostate cancer have symptomatic disease. This is true because there are no treatment options available with high effectiveness for cure of patients in this situation. Palliative therapy generally involves management of pain from bony metastases as well as diversionary treatment of obstructive uropathy either from local prostate cancer growth into the bladder base obstructing the ureters or retroperitoneal lymph node enlargement from metastatic disease.

Spinal cord compression

Spinal cord compression is a serious emergency for patients with advanced metastatic prostate cancer. For patients with evidence of spinal cord compression, immediate hormonal therapy should be instituted, preferably with ketoconazole 400 mg p.o. q.8 hours. Immediate orchiectomy is an alternative treatment. Patients who have previously received hormonal therapy should be treated with high dose steroids and subsequently receive neurosurgical consultation and consideration of emergent radiation therapy. Spinal cord compression may occur secondary to vertebral collapse from metastatic prostate cancer or epidural metastases. These can be effectively evaluated with MRI scans.

Palliative radiation therapy

Patients with isolated bony metastases that are symptomatic typically present with unrelenting, continuous localized pain. They may be effectively treated with localized radiation therapy of 3,000 cGy in 10 divided fractions (Porter et al., 1998). Patients should also be evaluated by an orthopedic surgeon. If a pathologic fracture has occurred in a weight-bearing region, surgical fixation is required for pain control and to allow healing. Post-operative irradiation may then be provided.

Systemic radionuclide therapy

For patients with extensive bony metastases that are symptomatic, systemic radionuclide therapy may be administered with good results. Strontium89 is quickly taken up in the mineral matrix of bone. The proportion of Strontium89 retained is directly related to the metastatic tumor burden and varies between 20 to 80 percent of the administered dose. Preferential accumulation occurs in and around metastatic bone deposits, where Strontium releases beta energy directly to the tumor. Elimination occurs through the kidneys, so careful disposal of urine is required for seven to 10 days after treatment. Patients who receive Strontium89 typically have myelosuppression with platelet counts decreasing 20 to 50 percent starting approximately three weeks after treatment. Strontium89 significantly delays the appearance of new, painful bony sites and also prolongs the time to the requirement of additional radiotherapy, compared to patients who received control treatments (Porter et al., 1993). Treatment may be repeated after three months. Buchali (1988) suggested a median survival advantage of more than eight months in patients who are treated with strontium89. Mertens et al. (1992) noted an eight month improvement in survival for patients treated with strontium89 in low dose cis-platin. However, a survival advantage for Strontium-treated patients has not been definitively demonstrated. Controlled trials are required to determine whether systemic radionuclide therapy provides any survival advantage over supportive care alone.

Medical management of hormone-refactory disease

Management of hormone refractory prostate cancer involves a difficult problem in management of the prostate cancer patient. Unfortunately, almost 40,000 men will die of prostate cancer per year, the second leading cause of cancer mortality in men in the United States. Previous trials for treatment of men with hormone refractory prostate cancer have been limited in their ability to demonstrate benefits.

Four steps may be considered in the management of hormone refractory prostate to decrease tumor growth. First, the maintenance of testicular androgen suppression should be confirmed. Castrate levels of testosterone should be reliably less than 50 ng/ml. Unfortunately, many patients who are on long-term GnRH-agonist therapy may have “acute on chronic” effects of GnRH agonist leading to biochemical flare of testosterone and PSA levels with recurrent treatment. If symptomatic disease is demonstrated in patients, or biochemical evidence of disease progression occurs related to repeat GnRH-depot treatments, then steps should be taken such as orchiectomy or shortening the interval of depot injections to confirm adequate androgen suppression. Secondly, antiandrogen therapy should be discontinued if it is in place. Antiandrogen withdrawal may result in clinical and PSA responses in up to 21 percent of men previously treated with the antiandrogens flutamide, bicalutamide, and megesterol acetate (Kelly and Scher, 1993). The phenomenon occurs within days of stopping flutamide, but may take up to six weeks after cessation of treatment with bicalutamide. The apparent agonist activity of flutamide has been suggested to occur as an activation of certain mutant androgen receptors present in prostate cancer cells (Fenton et al., 1997; Culig et al., 1997). Thirdly, second line hormonal therapy should be considered. For patients who have not previously received antiandrogens, antiandrogen therapy may be provided. Treatment of androgen-independent prostate cancer may respond to 150 to 200 mg of bicalutamide per day for about 25 percent of patients, after previously receiving flutamide therapy. Megesterol acetate has progestational activity that results in objective response rates of zero to nine percent and significant PSA declines in 12 to 14 percent of patients. Side effects may include thrombophlebitis and fluid retention. Adrenal androgen inhibitors such as aminoglutethamide or ketoconazole may also be applied in these patients with a low, partial response rate. Patients who are maintained on ketoconazole or aminoglutethamide should also receive hydrocortisone to prevent symptomatic systemic adrenal insufficiency. Estrogens and antiestrogens have also been applied to patients with hormone refractory prostate cancer. Up to three-quarters of patients treated with high-dose estrogen had effective pain relief, and approximately one-third had PSA declines of greater than 50 percent. This may be related to a direct mitotic arrest or cytotoxic effects on prostate cancer cells (Robertson et al., 1996).

An additional step is to consider chemotherapy for patients with hormone refractory prostate cancer. Unfortunately, even recent chemotherapy trials in hormone refractory prostate cancer have noted resulted in dramatic measurable responses for most patients. However, subjective responses can be noted. Apparently active agents can include estramustine, cyclophosphamide, etoposide, platinum, paclitaxel or adriamycin or vinblastine. The results of recent trials are summarized in Table (Oh and Kantoff, 1998). Adjunctive therapies with the use of systemic radiation have been previously discussed. In addition, investigational targets for therapy include growth-factor inhibitors, differentiation agents, cdk inhibitors, activators of apoptosis, antiangiogenesis agents, and immunotherapy including vaccines (Oh and Kantoff, 1998).

*

The challenge of the future for treatment of prostate cancer will involve development and application of effective treatments for systemic disease. It is fortunate that prostate cancer is so hormonally sensitive in its growth pattern, as this allows effective palliation for advanced disease. Chemotherapy currently offers palliative benefits to a small subset of patients; however, multi-drug combinations may offer some potential for curative treatment. Despite the promise of local therapies in decreasing the death rate from prostate cancer, management of advanced hormone refractory prostate cancer will remain an important issue for treatment of patients with this genitourinary disease

Observation (Expectant Management)

Patients who are followed expectantly should have regular physical examinations and serial PSA levels obtained. Progressive increases in PSA, development of local cancer growth as suggested by physical examination, or evidence of further metastatic disease should be evaluated.

Patients who are followed expectantly should have regular physical examinations and serial PSA levels obtained. Progressive increases in PSA, development of local cancer growth as suggested by physical examination, or evidence of further metastatic disease should be evaluated. For men with localized disease who demonstrate progression, repeat prostatic biopsies or treatment may be indicated. It is unclear how many patients can still be treated with curative intent after a period of observation and subsequent disease progression. It is understood and supported by the medical literature, that most men with localized prostate cancer and moderately well differentiated tumors, approximately 50 percent of these men who lived 15 years or more will die of prostate cancer, if no treatment is provided.

For men who have a limited life expectancy (less than ten years) either due to advanced age at diagnosis (typically greater than age 75) or significant co-morbidity, are therefore not candidates for treatment of localized prostate cancer with intent to cure. For patients who have mild co-morbidities and life expectancy greater than ten years, the risks and benefits of treatment should be balanced and the patient informed of his options including watchful waiting, radiation, and surgery. For men who have no significant co-morbidities, are young, and have a greater than 10- to 15-year life expectancy, all available data suggest that treatment is likely to be effective. Watchful waiting to determine if a cancer will progress is limited by the sensitivity of digital-rectal exam to detect cancer growth and the uncertain nature of PSA changes as patients have local cancer progression.

Despite its epidemic proportion of incidence, prostate cancer treatment still generates controversy. Prostate cancer treatment is associated with some degree of morbidity, may be applied to patients who have micrometastatic disease, and many patients at the time of diagnosis will have local disease that cannot be cured. Until 10- to 15-year data are available from early detection (PLCO) or treatment (PIVOT) studies for localized cancer, we will not have definitive information as to whether aggressive or conservative treatment should be provided for men with localized prostate cancer. However, the vast majority of prostate cancers that are detected as localized disease at this point are clinically important (Gardner et al., 1998). Slow but inevitable progression of clinically detected localized cancer occurs without treatment. Surgical treatment appears to be quite effective if cancers are detected early.

Radiation Therapy

Radiotherapy, the use of ionizing radiation to destroy cancer cells, has been proven to be effective in the treatment of many cancers.

RADIATION THERAPY

Radiotherapy, the use of ionizing radiation to destroy cancer cells, has been proven to be effective in the treatment of many cancers. Its role in the treatment of prostate cancer is somewhat limited by the relative radiation insensitivity of prostate cancer (Zelefsky et al., 1997). Radiation can be delivered by two modalities. It can be deilviered either as external beam radiotherapy in which an external tube delivers radiation directly to the prostate with little effect on surrounding tissues. A second approach to the treatment of localized prostate cancer is the administration of permanent implants such as 125iodine or 103palladium, known as brachytherapy. Brachytherapy with 125iodine has the potential advantage of delivering very high doses of local radiation therapy with a minimum of scatter and subsequent injury to surrounding structures such as bowel, bladder, and urethral sphincter/urethra. However, accurate placement of the implants is critical to delivery of radiation therapy.

Combinations of external-beam radiation therapy and brachytherapy have also been applied. Both external-beam radiation as well as brachytherapy have been enhanced in their effectiveness by the use of imaging modalities such as CT scans and transrectal ultrasound

Rapid evolution of prostate radiation therapy techniques has occurred over the past several years. Given the very long natural history and follow-up that is required to evaluate patients with localized prostate cancer for treatment effectiveness, very few patients have been treated with contemporary radiation techniques and had adequate follow-up

HORMONAL THERAPY WITH RADIATION

One approach to optimizing the effectiveness of radiation therapy is to decrease the amount of tumor present using pretreatment hormone therapy for three to six months prior to radiation treatment. Several large studies have looked at this issue and have found that pretreatment hormonal therapy prior to radiation therapy is more effective than radiation alone.

Radical Prostatectomy

Radical prostatectomy implies the complete removal of the prostate gland along with the pelvic lymph nodes. Radical prostatectomy may be performed by either a retropubic or perineal approach.

Radical prostatectomy implies the complete removal of the prostate gland along with the pelvic lymph nodes. Radical prostatectomy may be performed by either a retropubic or perineal approach. Most surgeons currently prefer the retropubic approach, as it allows access to the pelvic lymph nodes and simultaneous performance of a lymph node dissection. In addition, contemporary techniques for urethral anastomosis have very low complication rates with good continence, and wider excision or preservation of the neurovascular bundles may be more easily effected. Although perineal prostatectomy has the potential advantages of lower blood loss and more direct urethral anastomosis, these advantages may be outweighed by the lack of periprostatic fascias that are removed together with the prostate. During perineal prostatectomy, the dissection is performed essentially along the prostatic gland, whereas the primary dissection during retropubic prostatectomy is performed outside of the prostatic fascias.

Since its introduction by Millen in 1947, the retropubic approach to prostatectomy has been a standard treatment. However, the popularity of this procedure was poor until the last 20 years because of the frequent complications of bleeding, incontinence, and impotence. More recently, a series of anatomic discoveries have improved surgeons’ ability to remove all tumor and substantially decrease associated morbidity. Delineation of the periprostatic vascular anatomy, the relationship of the neurovascular bundles to the prostate, and subsequent evaluation of the periprostatic urethral sphincter mechanism have allowed a decrease in perioperative blood loss. In addition, improved rates of postoperative potency and urinary continence have been achieved. Many of these advances are based on anatomic work that was described by Walsh and others at the James Buchanan Brady Urological Institute of the Johns-Hopkins Hospital (Reiner & Walsh, 1979; Walsh et al., 1983; Walsh, 1987).

One major source of potential bleeding during prostatectomy is the dorsal vein complex that passes over the prostate gland. The dorsal vein complex enters the pelvis under the pubic bone. It is located just above the urethral sphincter muscles and below the periprostatic fascias. During division of the fascias and urethral sphincter, the dorsal vein complex is opened. Control of this vascular structure is usually performed with sutures. It must be performed carefully to avoid compromising urethral sphincter function. The dorsal vein complex from the penis then fans out over the prostate and it must be further secured on the lateral and superior portions of the prostate during completion of the prostatectomy (Reiner & Walsh, 1979).

The autonomic innervation of the penis travels in the cavernous nerves that are located just posterolateral to the prostate in close association with the lateral prostatic fascia and rectum. These nerves are derived from branches of the pelvic plexus that lies in a fenestrated plate along the lateral sidewall of the rectum between 5 and 11 cm from the anal verge. The pelvic plexus is derived of hypogastric nerves that travel lateral to the sigmoid colon as well as sacral roots 2, 3, and 4 that provide parasympathetic efferent preganglionic fibers. For patients in whom it is clinically appropriate to preserve the cavernous nerves, their location can be identified because they travel with the capsular veins of the prostate in a group posterolateral to the prostate. This neurovascular bundle complex is located outside of the prostate (Schlegel & Walsh, 1987). Preservation of the neurovascular bundle does not result in any compromise to removal of the entire prostate with its capsule.

During radical prostatectomy, the neurovascular bundle can be isolated and preserved by incising the lateral prostatic fascia just anterior to the neurovascular bundle. After small branches of the neurovascular bundle to the prostate are clipped and divided, the neurovascular bundle then stays on the rectal surface in close association with the lateral prostatic fascia, as the prostate is removed. The striated urethral sphincter surrounds the urethra and attaches to the prostate. Preservation of this urethral sphincter complex is critical to the early and effective restoration of continence for men after radical prostatectomy. Again, the striated urethral sphincter is outside of the prostate. Division of the striated urethral sphincter may be carried out under direct vision during apical dissection of the prostate. Direct incision of this region may be effected after dorsal vein complex control is obtained. Maintenance of an optimal length of urethral sphincter (striated) muscle is important. During all portions of the apical dissection, the surgeon must be certain that the entire prostate is removed, and only urethral muscle is preserved. Re-establishment of the striated urethral sphincter muscle relationship to the puboprostatic ligaments and periurethral fascias around the dorsal vein complex is important to provide normal anatomic relationship between the urethra and the pubis postoperatively.

PREOPERATIVE PREPARATION

Surgery is often deferred for six to eight weeks after needle biopsy of a prostate, and 12 weeks after transrectal resection to allow resolution of any inflammatory reaction that may occur from these biopsies. With the newer 18-gauge needle biopsies of the prostate, periurethral and periprostatic inflammation is typically minor. Some patients will choose to have autologous blood stored preoperatively or to receive recombinant erythropoietin preoperatively to decrease their risk of receiving heterologous blood transfusion. Patients may receive a limited bowel preparation with magnesium citrate and should have an enema on the morning prior to surgery. Many surgeons prefer a regional or a spinal anesthetic for this operation. Regional anesthesia is associated with lower blood loss and a decreased risk of deep venous thrombosis and pulmonary emboli. Since pulmonary emboli are the most common cause of perioperative mortality, use of epidural anesthesia is supported (Peters and Walsh, 1985; Malhotra et al., 1996). The patient is placed supine on the table, which is flexed to extend the distance between the umbilicus and the pubis. Position of table flexion is initially located at the level of the umbilicus. The patient is prepped and draped with the phallus available for manipulation during the procedure. A 16- to 18-French Foley catheter is placed per urethra with 40 to 50 cc in the Foley catheter balloon. A standard lower abdominal midline incision is fashioned and the retroperitoneal space is opened. Direct care should be taken to open the transversalis fascia sharply, as preservation of this structure may be important to prevent postoperative hernia formation. The peritoneum is then mobilized superiorly on both sides up to the level of the iliac vessels and psoas muscle, if lymph node dissection is planned.

SURGICAL PROCEDURE

Sampling lymph node dissection is performed in the obturator space with the lateral margin of dissection being the pelvic wall and external iliac vein, the distal margin being the node of Cloquet and the proximal margin being the hypogastric vessels. The posterior margin is the obturator nerve within the pelvis. Removal of the obturator vessels is neither helpful nor beneficial. In occasional cases, the obturator artery provides blood supply to the phallus and removal of the obturator artery may compromise penile blood flow. A self-retaining retractor, such as the Balfour retractor, is used during the procedure. A retracting arm with a notched blade, such as the Yu-Holtgrewe blade, can then be used to retract the Foley catheter within the bladder superiorly. This provides optimal access to the prostate and its attachments to the pubis. The endopelvic fascia is then defined by removing any fat from this structure, and an incision is fashioned sharply in the endopelvic fascia just lateral to the capsular veins of the prostate. Care should be taken during this time to incise only the fascia. This incision allows separation of the endopelvic muscles from the prostate. Small veins in this region may be controlled with electrocautery. After incision in the endopelvic fascia on both sides, the prostate can now be moved laterally to allow better access to the apex. At this point, a running suture of 0 or 20 chromic can be placed into the fascia overlying the prostate from the midportion of the prostate laterally on each side over its anterior surface. This allows the dorsal vein vessels to be trapped between the fascia and the prostate itself. This maneuver decreases back bleeding through the dorsal venous complex over the prostate. The fascia covering the prostate is then divided sharply, which includes division of the puboprostatic ligaments. Separation of the puboprostatic ligaments from the pubic symphysis is discouraged, as this prevents re-establishment of the normal urethral sphincter relationship to the pubic bone through its reattachment to the periurethral fascias. The dorsal vein complex is then entered and oversewn with 2-0 or 3-0 absorbable sutures (Figure). As noted above, care must be taken to avoid extending these sutures into the urethral sphincter complex, as this may limit its function postoperatively. The striated urethral sphincter and anterior urethra are then divided just distal to the apex of the prostate. Removal of an excess length of urethral sphincter muscle does not improve cancer control, and can increase the risk of postoperative incontinence. Care should be taken to divide the urethral muscle around the Foley catheter. The posterior portion of the urethra is not directly visualized at this point and is not divided. The urethral sphincter sutures can then be placed for the subsequent urethro-vesicle anastomosis. Viewed from the patient’s head, sutures are placed at 6 o’clock, 8 o’clock, 10 o’clock, 12 o’clock, 2 o’clock, and 4 o’clock. Placement of the sutures at this time is easy to effect, by pushing the prostate inferiorly and sutures are placed in an inside-out fashion only for the 12 o’clock suture and other sutures are placed in an outside-in fashion. For the anterior sutures, the urethral mucosa and a small cross-segment of urethral muscle is included in the suture as well as the anterior segment of fascia that was previously above the urethral sphincter. This allows restoration of the normal urethral angle postoperatively. After five of these six sutures have been placed, the catheter is then brought up through the incision in the urethra and retracted cephalad. The 6 o’clock suture can then be placed in the posterior urethra. A right-angle clamp is placed behind the urethra and the posterior segment of urethra is divided sharply. Attention may then be turned to the lateral prostatic fascias.

The prostate is rolled laterally without excessive traction on the urethral catheter. The lateral prostatic fascia alone is divided just above the neurovascular bundle complex at the posterolateral level of the prostate. Small vessels are identified and clipped which come off of the neurovascular bundle. The prostate should then be released from the neurovascular bundle starting at the apical level (Figure). The Denonvilliers’ fascia can then be easily identified and a right-angle clamp is placed behind Denonvilliers’ fascia and behind the posterior portion of the urethral sphincter muscle at the level of the apical prostate. Care must be taken at this point to avoid an incision into the posterior portion of the prostate. Blunt dissection on the rectum at this point should be avoided to prevent tearing or neuropraxia to the neurovascular bundles. While neurovascular bundles are still attached to the prostate, they are highly susceptible to traction injury. The Denonvilliers’ fascia is then incised just medial to the neurovascular bundle, freeing the bundle from the prostate.

In cases where it is appropriate to unilaterally or bilaterally perform wide excision of the neurovascular bundle, the neurovascular bundle is isolated at the level at the apex of the prostate and absorbable sutures are used to tie this neurovascular bundle complex. A right angle should be placed completely around the neurovascular bundle with care taken to avoid entry into the rectum at this point. Incision in the lateral prostatic fascia for wide excision of the neurovascular bundle is performed posterior to the bundle itself.

After the urethral sphincter is divided posteriorly Denonvilliers’ fascia, the prostate may then be mobilized up to the level of the posterolateral base of the prostate near its junction with the bladder. Major vessels, branches of the inferior vesicle artery entering the prostate should be secured at this level with clips or ligatures. After the prostate is mobilized laterally, Denonvilliers’ fascia is then incised over the level of the seminal vesicles. This allows dissection to be performed along the seminal vesicles up laterally over the bladder. An arterial complex is typically found just anterior to the seminal vesicle on each side, between the seminal vesicle and the bladder. This arterial complex should be specifically ligated before its division. Attention may then be turned to the anterior surface of the junction of the bladder and the prostate. The bladder is entered with care taken to avoid entry into the prostate. The best maneuver to avoid entry into the prostate is to maintain dissection on the bladder muscle itself. Once the bladder has been widely opened the Foley catheter balloon may be deflated and both ends of the Foley catheter used to retract the prostate inferiorly.

After intravenous infusion of indigo carmine, blue efflux from the ureteral orifices may be directly identified. This can be used to avoid incision into the ureteral orifices. The bladder muscle may then be divided posteriorly, leaving the prostate specimen attached only by its seminal vesicles and vas deferens. Midline dissection is then performed to isolate the vas deferens that is separated off of the seminal vesicle along its entire length. Separation of the vas from the seminal vesicle allows identification of the vessels at the superior margin of the seminal vesicles. The vas deferens and its associated vessels are clipped and divided. Attention is then turned to the seminal vesicles that are dissected down to their vessels that are located at the superior portion of the seminal vesicles. Care must be taken to avoid avulsion of these vessels or the seminal vesicle. Seminal vesicle blood supply is clipped and divided, and the prostate specimen can be removed. An initial review for bleeding within the pelvis should be performed. The bladder neck can then be narrowed in a tennis-racquet fashion. Initial sutures of 2-0 chromic are placed at the level of the ureteral orifices to re-approximate the bladder muscle. The bladder is closed along its length. An approximately 30-French opening is left at the anterior portion of the bladder neck closure. The urethral mucosa can be everted with 4-0 sutures to improve the opportunity for mucosa-to-mucosa anastomotic connection postoperatively (Figure). The sutures that were previously placed into the urethra can then be placed in a corresponding fashion at 12-, 2-, 4-, 6-, and 10 o’clock. These sutures are placed after a new urethral catheter has been placed and brought up anteriorly within the pelvis. The Foley catheter is placed into the bladder prior to placement of the 12 o’clock suture, but after placement of all other sutures.

The urethro-vesical anastomosis is then completed by tying each of the sutures circumferentially around the urethro-vesical anastomosis. I prefer to use 2-0 or 3-0 Monocryl sutures for the anastomosis, as they tie easily, are fairly rapidly absorbed after healing of the anastomosis, and are durable sutures. There should be no gaps in the anastomosis and the bladder should come down easily. If there is difficulty in bringing the bladder down to the urethra, the obliterated umbilical artery should be divided, the flexion should be decreased on the operating table, and the peritoneal reflection should be freed up laterally to allow the bladder to more easily reach the urethra without tension.

Pelvic drains may then be placed into the lower abdomen to collect any urethral leakage that may occur from the anastomosis perioperatively as well as lymphatic fluid. If clinically detectable hernias are present, these may be repaired at this time. Simultaneous preperitoneal repair of hernias in men who are undergoing radical prostatectomy may be effectively accomplished with polypropylene mesh with low morbidity and excellent results (Choi et al., 1999).

PERINEAL PROSTATECTOMY

The perineal prostatectomy is performed with the patient in the exaggerated lithotomy position. The perineum is opened, and dissection is performed around the external rectal sphincter fibers. The rectourethralis muscle is divided, and Denonvilliers’ fascia is left on the prostate (Figure). The vascular pedicles to the prostate are ligated at the prostate base, the seminal vesicles and vasa deferentia are isolated and removed, and the prostate is separated from the bladder. Anastomosis is carried out to the urethral stump after removal of the prostate.

RESULTS AFTER PROSTATECTOMY

Patients after radical prostatectomy should have an undetectable PSA level. Systemic PSA detection (>0.2 ng/mL) is indicative of recurrent local or systemic disease. The risk of biochemical recurrence is dependent on the local extent of tumor (organ confined vs. extracapsular penetration), invasion of seminal vesicles or lymph nodes and Gleason sum score. Long term overall results from Johns Hopkins Hospital are presented in Figure . However, Gleason score and extent of local disease in the prostatic specimen provides a far more accurate means of estimating the risk of disease recurrence (Pound et al. 1997).

Results for return of urinary control after prostatectomy vary greatly from surgeon to surgeon in different series, urinary control returns for 75-98% of patients postoperatively. Return of erectile function may take up to 12-18 months, and achievement of erections adequate for vaginal penetration and climax occur in 40-80% of men in selected series, based on the number of neurovascular bundles preserved, age of the patient, preoperative erectile function, and extent of tumor.

CARE OFFERED FOR PROSTATE CANCER

Prostate cancer is the commonest malignancy affecting males. We at SCUG specialises in diagnosing and treating prostate cancer to the highest standards. Prostate cancer is suspected if there is hard prostate during digital rectal examination and Prostate Specific Antigen level is increased in blood.

At our centre we do Trans Rectal Ultra Sound(TRUS) guided biopsy of prostate to diagnose cancer. We appropriately stage the disease and offer treatment suitable for each stage. Options are

  1. Laparoscopic Radical Prostatectomy. (complete removal of cancer containing prostate)
  2. Hormonal treatment in the form of removal of testes or injections(LHRH) in advanced disease.
  3. Palliative care in terminally ill patients.

For details about the condition and procedures, refer to our section on clinical condition.