Prostate Cancer

WHAT IS THE PROSTATE CANCER?

Prostate cancer is a disease in which malignant (cancer) cells form in the tissues of the prostate.

The prostate is a gland in the male reproductive system located just below the bladder (the organ that collects and empties urine) and in front of the rectum (the lower part of the intestine). It is about the size of a walnut and surrounds part of the urethra (the tube that empties urine from the bladder). The prostate gland produces fluid that makes up part of the semen.

Carcinoma of the prostate is predominantly a tumor of older men, which frequently responds to treatment when widespread and may be cured when localized. The rate of tumor growth varies from very slow to moderately rapid, and some patients may have prolonged survival even after the cancer has metastasized to distant sites such as bone. Because the median age at diagnosis is 72 years, many patients—especially those with localized tumors—may die of other illnesses without ever having suffered significant disability from their cancer. The approach to treatment is influenced by age and coexisting medical problems. Side effects of various forms of treatment should be considered in selecting appropriate management.



HOW TO DETECT PROSTATE CANCER?

Possible signs of prostate cancer include a weak flow of urine or frequent urination.

Prostate cancer should be suspected if any of the following problems occur:

Weak or interrupted flow of urine.
Frequent urination (especially at night).
Difficulty urinating.
Pain or burning during urination.
Blood in the urine or semen.
Nagging pain in the back, hips, or pelvis.
Painful ejaculation.
Tests listed as below are used to detect prostate cancer.

Digital rectal exam (DRE): An exam of the rectum may detect the prostate through the rectal wall for lumps or abnormal areas.
Prostate-specific antigen (PSA) test: PSA is a substance made by the prostate that may be found in an increased amount in the blood of men who have prostate cancer. PSA levels in the blood may also be high in men who have an infection or inflammation of the prostate or BPH (an enlarged, but noncancerous, prostate).
Transrectal ultrasound: Transrectal ultrasound may shows abnormal echo of cancer in prostate and may be used to take a biopsy.
Biopsy: The biopsy may be performed through transrectal or transperineal routes for pathological diagnosis of prostate cancer.The Gleason score ranges from 2-10 and describes how likely it is that a tumor will spread. The lower the number, the less likely the tumor is to spread.


HOW TO TREAT PROSTATE CANCER?

State-of-the-art treatment in prostate cancer provides prolonged disease-free survival for many patients with localized disease but is rarely curative in patients with locally extensive tumor. Even when the cancer appears clinically localized to the prostate gland, a substantial fraction of patients will develop disseminated tumor after local therapy with surgery or irradiation.

Stage I Prostate Cancer

Stage I prostate cancer is defined by American Joint Committee on Cancer (AJCC) TNM classification: T1a, N0, M0, G1 (Gleason 2-4).

The frequency of clinically silent, nonmetastatic prostate cancer that can be found at autopsy greatly increases with age and may be as high as 50% to 60% in men aged 90 years and older. Many stage I cancers are well-differentiated and only focally involve the gland (T1a, N0, M0); most require no treatment other than careful follow-up.

In younger patients (aged 50-60 years) whose expected survival is long, treatment should be considered. Less-differentiated cancers that involve more than a few pieces of resected tissue (T1b, N0, M0) are biologically more aggressive.

Standard treatment options:

Careful observation without further immediate treatment in selected patients.
External-beam radiation therapy. Definitive radiation therapy should be delayed 4 to 6 weeks after transurethral resection to reduce incidence of stricture.
Radical prostatectomy, usually with pelvic lymphadenectomy. Radical prostatectomy may be difficult after a transurethral resection of the prostate. Consideration may be given to postoperative radiation therapy for patients who are found to have capsular penetration or seminal vesicle invasion by tumor at the time of prostatectomy or who have a detectable level of prostate-specific antigen more than 3 weeks after surgery.
Interstitial implantation of radioisotopes (i.e., I-125, palladium, iridium) done through a transperineal technique with either ultrasound or computed tomography (CT) guidance is being done in carefully selected patients with T1 or T2A tumors. Short-term results in these patients are similar to those for radical prostatectomy or external-beam radiation therapy. One advantage is that the implant is performed as outpatient surgery. The rate of maintenance of sexual potency with interstitial implants has been reported to be 86% to 92%, which compares with rates of 10% to 40% with radical prostatectomy and 40% to 60% with external-beam radiation therapy; however, urinary tract frequency, urgency, and less commonly, urinary retention are seen in most patients but subside with time. Rectal ulceration may also be seen. This risk decreased with increased operator experience and modification of implant technique.
Stage II Prostate Cancer

Stage II prostate cancer is defined by American Joint Committee on Cancer (AJCC) TNM classifications:

T1a, N0, M0, G2 (Gleason 3-4).
T1b, N0, M0, any G.
T1c, N0, M0, any G.
T1 (not further specified), N0, M0, any G.
T2, N0, M0, any G.
Standard treatment options:

Radical prostatectomy, usually with pelvic lymphadenectomy. If allowed by the extent of tumor, anatomical dissection that preserves nerves necessary for erection avoids impotence postoperatively in some patients. Consideration may be given to postoperative radiation therapy for patients who are found to have capsular penetration or seminal vesicle invasion by tumor at the time of prostatectomy or a detectable level of prostate-specific antigen more than 3 weeks after surgery. Postoperative radiation therapy does reduce local recurrence.
External-beam irradiation. Prophylactic irradiation of clinically or pathologically uninvolved pelvic lymph nodes does not appear to improve overall survival or prostate cancer-specific survival. Definitive radiation therapy should be delayed 4 to 6 weeks after transurethral resection to reduce incidence of stricture. For patients with bulky T2b tumors, adjuvant hormonal therapy should be considered.
Careful observation without further immediate treatment (in selected patients).
Interstitial implantation of radioisotopes (i.e., I-125, palladium, iridium) done through a transperineal technique with either ultrasound or computed tomography guidance is being done in carefully selected patients with T1 or T2A tumors.

External-beam radiation therapy designed to decrease exposure of normal tissues using methods such as CT-based 3-D conformal treatment planning is under clinical evaluation.
Ultrasound-guided percutaneous cryosurgery is alternative modality. Other clinical trials, including trials of neoadjuvant hormonal therapy followed by radical prostatectomy.
Stage III Prostate Cancer

Stage III prostate cancer is defined by American Joint Committee on Cancer TNM classification: T3, N0, M0, any G.

Standard treatment options

External-beam radiation. Hormonal therapy should be considered in addition to external-beam radiation. Moreover, although Radiation Therapy Oncology Group Trial 9413 showed an increased progression-free survival at 4 years for patients with a 15% estimated risk of lymph node involvement receiving whole-pelvic irradiation as compared with prostate-only irradiation, overall survival and PSA failure rates were not significantly different. Definitive radiation therapy should be delayed until 4 to 6 weeks after transurethral resection to reduce incidence of stricture. Radiation therapy designed to decrease exposure of normal tissues using methods such as computed tomography-based 3-D conformal treatment planning is under clinical evaluation.
Hormonal manipulations (orchiectomy or LHRH agonist).
Radical prostatectomy, usually with pelvic lymphadenectomy (in highly selected patients). Consideration may be given to postoperative radiation therapy for patients who are found to have capsular penetration or seminal vesicle invasion by tumor at the time of prostatectomy or a detectable level of prostate-specific antigen more than 3 weeks after surgery. The role of preoperative (neoadjuvant) hormonal therapy is not established at the present time.
Careful observation without further immediate treatment.
Symptomatic treatment

Since many stage III patients have urinary symptoms, control of symptoms is an important consideration in treatment. This may often be accomplished by radiation therapy, radical surgery, transurethral resection of the prostate, or hormonal manipulation.

1.Radiation therapy: External-beam radiation therapy designed to decrease exposure of normal tissues using methods such as computed tomography-based 3-D conformal treatment planning is under clinical evaluation.

2.Hormonal manipulations: effectively used as initial therapy for prostate cancer:

Orchiectomy.
Leuprolide or other LHRH agonists (Zoladex) in daily or depot preparations .
Estrogen (diethylstilbestrol [DES] is no longer available).
Nonsteroidal antiandrogen (e.g., flutamide, nilutamide, bicalutamide) or steroidal antiandrogen (cyproterone acetate).
A meta-analysis of randomized trials comparing various hormonal monotherapies in men with stage III or IV prostate cancer (predominantly stage IV) came to the following conclusions:

Overall survival at 2 years using any of the LHRH agonists is similar to treatment with orchiectomy or 3 mg per day of DES (HR=1.26, 95% CI=0.92-1.39).
Survival rates at 2 years are similar or worse with nonsteroidal antiandrogens compared to orchiectomy (HR=1.22, 95% CI=0.99-1.50).
Treatment withdrawals, used as a surrogate for adverse effects, occurred less with LHRH agonists (0%-4%) than with nonsteroidal antiandrogens (4%-10%).
3.Palliative surgery: (transurethral resection).

4.Interstitial implantation combined with external-beam radiation therapy is being used in selected T3 patients.

5.Mixed-beam (neutron/photon) radiation therapy: A

randomized trial reported improved local control and survival with mixed-beam (neutron/photon) radiation therapy, compared to standard photon radiation therapy. A subsequent randomized study from the same group compared fast-neutron radiation therapy to standard photon radiation therapy. Local-regional control was improved with neutron treatment. Proton-beam radiation therapy is also under investigation.

6.Ultrasound-guided percutaneous cryosurgery: is an

alternative modality which involves destruction of prostate cancer cells by intermittent freezing of the prostate tissue with cryoprobes, followed by thawing.

Stage IV Prostate Cancer

Stage IV prostate cancer is defined by American Joint Committee on Cancer (AJCC) TNM classifications:

T4, N0, M0, any G.
Any T, N1, M0, any G.
Any T, any N, M1, any G.
Hormonal treatment is the mainstay of therapy for distant metastatic (stage D2) prostate cancer. Cure is rarely, if ever, possible, but striking subjective or objective responses to treatment occur in most patients.

In some series, pretreatment levels of prostate-specific antigen (PSA) are inversely correlated with progression-free duration in patients with metastatic prostate cancer who receive hormonal therapy. After hormonal therapy is instituted, reduction of PSA to undetectable levels provides information regarding the duration of progression-free status. Orchiectomy and estrogens yield similar results, and selection of 1 or the other depends on patient preference and the morbidity of expected side effects. Estrogens are associated with the development or exacerbation of cardiovascular disease, especially in high doses. Diethylstilbestrol (DES) in a dose of 1 mg per day is not associated with as frequent cardiovascular complications as higher doses are; however, the use of DES has decreased because of cardiovascular toxic effects, and DES is no longer commercially available in the United States. The psychologic implications of orchiectomy are objectionable to many patients, and many will choose alternative therapy if effective. Combined orchiectomy and estrogens are not indicated to be superior to either treatment administered alone.

Approaches using LHRH agonists and/or antiandrogens in patients with stage IV prostate cancer have produced response rates similar to standard hormonal treatments. The LHRH analog leuprolide (1 mg subcutaneously every day) was found to be as effective as DES (3 mg orally every day) in any T, any N, M1 patients, but caused less gynecomastia, nausea/vomiting, and thromboembolisms. The depot LHRH analog goserelin (Zoladex) was found to be as effective as orchiectomy or DES at a dose of 3 mg per day. A depot preparation of leuprolide (Depo Lupron), which is therapeutically equivalent to leuprolide, is available as a monthly or 3-monthly depot. Castration has been shown to be superior to monotherapy with bicalutamide. A comparison of 1 mg of DES orally 3 times per day to 250 mg of flutamide 3 times per day in patients with metastatic prostate cancer showed similar response rates with both regimens but superior survival with DES. More cardiovascular and/or thromboembolic toxic effects of borderline statistical significance were associated with the DES treatment.

On the basis that the adrenal glands continue to produce androgens after surgical or medical castration, case series studies were performed in which antiandrogen therapy was added to castration. Promising results from such case series led to widespread use of the strategy, known as “maximal androgen blockage” (MAB) or “complete androgen blockade.” However, subsequent randomized controlled trials cast doubt on the efficacy of adding an antiandrogen to castration.

When trials of androgen suppression versus androgen suppression plus either nilutamide or flutamide were examined in a subset analysis, the absolute survival rate at 5 years was better for the combined therapy group (2.9% better, 95% CI=0.3%-5.5%); however, when trials of androgen suppression versus androgen suppression plus cyproterone acetate were examined, the absolute survival trend at 5 years was worse for the combined therapy group (2.8% worse, 95% CI= -7.6% to +2.0%).

Clinical trial evidence of single hormonal therapies and combined androgen blockade was performed in men with stage III or IV prostate cancer (predominantly stage IV) and came to the following conclusions:

Overall survival at 2 years using any of the LHRH agonists is similar to treatment with orchiectomy or 3 mg per day of DES (HR=1.26, 95% CI=0.92-1.39).
Survival rates at 2 years are similar or worse with nonsteroidal antiandrogens compared to orchiectomy (HR=1.22, 95% CI=0.99-1.50).
Treatment withdrawals, used as a surrogate for adverse effects, occurred less with LHRH agonists (0%-4%) than with nonsteroidal antiandrogens (4%-10%).
Combined androgen blockade was of no greater benefit than single hormonal therapy, with less patient tolerance.

After tumor progression on 1 form of hormonal manipulation develops, an objective tumor response to any other form is uncommon. However, some studies suggest that withdrawal of flutamide (with or without aminoglutethimide administration) is associated with a decline in PSA values and that one may need to monitor for this response before initiating new therapy. To date, no evidence indicates that chemotherapy prolongs survival. Low-dose prednisone may palliate symptoms in about one third of cases.

PC-SPES is an herbal combination stated to contain 8 herbs: chrysanthemum, isatis, licorice, lucid ganoderma, pseudo-ginseng, rubescens, saw palmetto, and scute. Although it was marketed as a dietary supplement for “prostate health,” it was frequently used with therapeutic intent by prostate cancer patients. (“PC” stood for “prostate cancer;” “SPES” is Latin for “hope”). Several uncontrolled case series showed some clinical activity as manifested by reduction in PSA, as well as loss of libido and sexual potency, gynecomastia, and thromboembolism. This led to the hypothesis that its clinical activity could be due to natural or synthetic compounds with estrogenic activity.

Standard treatment options:

Hormonal manipulations effectively used as initial therapy for prostate cancer:
Orchiectomy alone or with an androgen blocker.
LHRH agonists such as leuprolide in daily or depot preparations. (These agents may be associated with tumor flare when used alone; therefore, the initial concomitant use of antiandrogens should be considered in the presence of liver pain, ureteral obstruction, or impending spinal cord compression.)
Leuprolide plus flutamide; however, the addition of an antiandrogen to leuprolide has not been shown to improve survival in a meta-analysis.
Estrogens (DES, chlorotrianisene, ethinyl estradiol, conjugated estrogens U.S.P., DES-diphosphate). (DES is no longer commercially available in the United States.)
External-beam irradiation.
Palliative radiation therapy.
Palliative surgery (transurethral resection).
Recurrent Prostate Cancer

In prostate cancer, the selection of further treatment depends on many factors, including previous treatment, site of recurrence, coexistent illnesses, and individual patient considerations. Definitive radiation therapy can be given to patients who fail only locally following prostatectomy. An occasional patient can be salvaged with prostatectomy after a local recurrence following definitive radiation therapy; however, only about 10% of patients treated initially with radiation will have local relapse only. In these patients, prolonged disease control is often possible with hormonal therapy, with median cancer-specific survival of 6 years after local failure. Cryosurgical ablation of recurrence following radiation is associated frequently with elevated prostate-specific antigen (PSA) and a high complication rate. This technique is still undergoing clinical evaluation. Most relapsing patients who initially received locoregional therapy with surgery or irradiation will fail with disseminated disease and are managed with hormonal therapy. The management of these patients with stage IV disease is discussed in the preceding section. Palliative radiation therapy for bone pain can be very useful. Because of the poor prognosis in prostate cancer patients with relapsing or progressive disease after hormonal therapy, clinical trials are appropriate. These include phase I and II trials of new chemotherapeutic or biologic agents.

Even among patients with metastatic “hormone-refractory prostate cancer,” there is some heterogeneity in prognosis and in retained hormone sensitivity. In such patients who have symptomatic bone disease, several factors are associated with worsened prognosis: poor performance status, elevated alkaline phosphatase, abnormal serum creatinine, and short (<1 year) previous response to hormone therapy. The absolute level of PSA at the initiation of therapy in relapsed or hormone-refractory patients has not been shown to be of prognostic significance. Some patients whose disease has progressed on combined androgen blockade can respond to a variety of second-line hormonal therapies. Aminoglutethimide, hydrocortisone, flutamide withdrawal, progesterone, ketoconazole, and combinations of these therapies have produced PSA responses in 14% to 60% of patients treated and have also produced clinical responses of 0% to 25% when assessed. The duration of these PSA responses has been in the range of 2 to 4 months. Survival rates are similar whether ketoconazole plus hydrocortisone is initiated at the same time as anti-androgen (e.g., flutamide, bicalutamide, or nilutamide) withdrawal or when PSA has risen after an initial trial of anti-androgen withdrawal. Data on whether PSA changes while on chemotherapy are predictive of survival are conflicting.

Patients treated with either luteinizing hormone agonists or estrogens as primary therapy are generally maintained with castrate levels of testosterone.

Painful bone metastases can be a major problem in prostate cancer. Many strategies have been studied for palliation, including pain medication, radiation, corticosteroids, bone-seeking radionuclides, gallium nitrate, and bisphosphonates. External-beam radiation therapy for palliation of bone pain can be very useful. Also, the use of radioisotopes such as strontium-89 has been shown to be effective as palliative treatment of some patients with osteoblastic metastases. When this isotope is given alone, it has been reported to decrease bone pain in 80% of patients treated and is similar to responses with local or hemibody radiation. When used as an adjunct to external-beam radiation therapy, strontium-89 was shown to slow disease progression and to reduce analgesic requirements, compared to external-beam radiation therapy alone.

A multicenter randomized trial of a single intravenous dose of Strontium89 chloride (150 MBq: 4 mCi) versus palliative external-beam radiation in men with painful bone metastases from prostate cancer despite hormone treatment showed similar subjective pain response rates: 34.7% versus 33.3%, respectively. Overall survival was better in the external-beam radiation group than in the Strontium89 chloride group (P=0.046; median survival 11.0 vs. 7.2 months). No statistically significant differences in time-to-subjective progression or in progression-free survival were seen.

Chemotherapy has been reported to provide palliative benefit to some men with hormone-refractory disease. Low-dose prednisone may palliate symptoms in some patients. In a randomized comparison of prednisone (5 mg 4 times per day) with flutamide (250 mg 3 times per day) in patients with disease progression after androgen ablative therapy (castration or luteinizing hormone-releasing hormone [LHRH] agonist), prednisone and flutamide produced similar survival, symptomatic response, PSA response, and time to progression; however, there were statistically significant differences in pain, nausea and vomiting, and diarrhea in patients who received prednisone. A randomized trial showed improved pain control in hormone-resistant patients treated with mitoxantrone plus prednisone compared with those treated with prednisone alone. Differences in overall survival or measured global quality of life between the 2 treatments were not statistically significant.

Currently, no chemotherapy regimen can be considered as standard.



HOW TO DETECT THE PROGNOSIS OF PROSTATE CANCER?

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis (chance of recovery) depends on the following:

The stage of the cancer (whether it affects part of the prostate, involves the whole prostate, or has spread to other places in the body).
The patient’s age and health.
Whether the cancer has just been diagnosed or has recurred (come back).
Survival of the patient with prostatic carcinoma is related to the extent of the tumor. When the cancer is confined to the prostate gland, median survival in excess of 5 years can be anticipated. Patients with locally advanced cancer are not usually curable, and a substantial fraction will eventually die of their tumor, although median survival may be as long as 5 years. If prostate cancer has spread to distant organs, current therapy will not cure it. Median survival is usually 1 to 3 years, and most such patients will die of prostate cancer. Even in this group of patients, however, indolent clinical courses lasting for many years may be observed.

Other factors affecting the prognosis of patients with prostate cancer that may be useful in making therapeutic decisions include histologic grade of the tumor, patient’s age, other medical illnesses, and level of PSA. Poorly differentiated tumors are more likely to have already metastasized by the time of diagnosis and are associated with a poorer prognosis. For patients treated with radiation therapy, the combination of clinical tumor (T) stage, Gleason score, and pretreatment PSA level can be used to more accurately estimate the risk of relapse. In most studies, flow cytometry has shown that nuclear DNA ploidy is an independent prognostic indicator for progression and for cause-specific survival in patients with pathologic stages C and D1. Diploid tumors have a more favorable outcome than either tetraploid or aneuploid tumors. The use of flow cytometry techniques and histogram analysis to determine prognosis will require standardization.

Several nomograms have been developed to predict outcomes either prior to or after radical prostatectomy with intent to cure. Preoperative nomograms are based on clinical stage, PSA, and Gleason score. Postoperative nomograms add pathologic findings, such as capsular invasion, surgical margins, seminal vesicle invasion, and lymph node involvement. The nomograms, however, were developed at academic centers and may not be as accurate when generalized to nonacademic hospitals, where the majority of patients are treated. In addition, the nomograms use nonhealth (intermediate) outcomes such as PSA rise or pathologic surgical findings, and subjective endpoints such as the physician's perceived need for additional therapy. In addition, the nomograms may be affected by changing methods of diagnosis or neoadjuvant therapy over time.

Definitive treatment is usually considered for younger men with prostate cancer and no major comorbid medical illnesses because younger men are more likely to die of prostate cancer than older men or men with major comorbid medical illness. Elevations of serum acid phosphatase are associated with poor prognosis in both localized and disseminated disease. PSA, an organ-specific marker with greater sensitivity and high specificity for prostate tissue, is often used as a tumor marker. After radical prostatectomy, detectable PSA levels identify patients at elevated risk of local treatment failure or metastatic disease; however, a substantial proportion of patients with elevated or rising PSA levels after surgery may remain clinically free of symptoms for extended periods of time. Therefore, biochemical evidence of failure on the basis of elevated or slowly rising PSA alone may not be sufficient to alter treatment. For example, in a retrospective analysis of nearly 2,000 men who had undergone radical prostatectomy with curative intent and who were followed for a mean of 5.3 years, 315 men (15%) demonstrated an abnormal PSA ≥0.2 ng/mL, felt to be evidence of “biochemical recurrence.” Of these 315 men, 103 men (34%) developed clinical evidence of recurrence. The median time to development of clinical metastasis after biochemical recurrence was 8 years. After the men developed metastatic disease, the median time to death was an additional 5 years.

After radiation therapy with curative intent, persistently elevated or rising PSA may be a prognostic factor for clinical disease recurrence; however, reported case series have used a variety of definitions of “PSA failure.” It is difficult to base decisions about instituting additional therapy on biochemical failure. The implication of the various definitions of “PSA failure” for overall survival is not known, and as in the surgical series, many biochemical relapses (rising PSA alone) may not be clinically manifested in patients treated with radiation.

Preliminary data from a retrospective cohort of patients with clinically localized prostate cancer treated with either radical prostatectomy or radiation therapy suggested that short posttreatment PSA doubling time (<3 months in this study) is a useful surrogate endpoint for all-cause mortality and prostate cancer mortality after surgery or radiation. This observation should be independently confirmed in a prospective study design and may not apply to patients treated with hormonal therapy.

After hormonal therapy, reduction of PSA to undetectable levels provides information regarding the duration of progression-free status; however, decreases in PSA of less than 80% may not be very predictive. Yet, because PSA expression itself is under hormonal control, androgen deprivation therapy can decrease the serum level of PSA independent of tumor response. Therefore, clinicians cannot rely solely on the serum PSA level to monitor a patient’s response to hormone therapy; they must also follow clinical criteria.