Prostate cancer is one of the most common malignancies diagnosed in men and is the most common cancer found in men older than 60 years. The incidence of prostate cancer increases markedly with age. In fact, the incidence is exponentially related to age. The number of men with latent prostate cancer is the same across all cultures, races, and ethnic groups, but the frequency of clinically active cancer is markedly different. With the development of prostate-specific antigen (PSA) screening, more men are identified earlier as having prostate cancer.
Incidence and mortality rates vary widely throughout the world, with the highest reported incidence in black American men. South American countries, such as Brazil, and Scandinavian countries, such as Sweden and Norway, also have high reported incidences, whereas Asian countries such as Japan and China report low incidences.
Anatomy: McNeal first proposed the histologic division of the prostate into peripheral zone (PZ), a central zone (CZ), and an inner transitional zone (TZ). In the young adult prostate, approximately 5% of prostatic glandular tissue is in the TZ located on both sides of the prostatic urethra.
The PZ constitutes 70% of the prostate and lies on the posterior and lateral aspects of the gland surrounding the TZ. Of all prostate cancers, 70% occur in the PZ, and approximately 20% occur in the TZ.
Histology
Adenocarcinomas- 95%
Transitional cell carcinomas-4%
Other rare histopathologic types of prostate carcinoma include small cell carcinoma, mucinous carcinoma, endometrioid cancer (prostatic ductal carcinoma), squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), and signet-ring cell carcinoma. And neuroendocrine tumors.
Histological Grading
The most commonly used system of classifying histologic characteristics of prostate cancer is the Gleason score, which is determined by the glandular architecture within the tumor.The predominant pattern and the second most common pattern are given grades from 1-5. The sum of these 2 grades is referred to as the Gleason score. Scoring based on the 2 most common patterns is an attempt to factor in the considerable heterogeneity within cases of prostate cancer.
Grades are based on the extent to which the epithelium assumes a normal glandular structure. A grade of 1 indicates a near-normal pattern, and grade 5 indicates the absence of any glandular pattern .This scheme of grading histological features is highly dependent on the skill and experience of the pathologist and is subject to some degree of individual variation.
· A score of 2-4 is considered low grade or well differentiated.
· A score of 5-7 is considered moderate grade or moderately differentiated.
· A score of 8-10 is considered high grade or poorly differentiate
Clinical presentation
Patients with prostate cancer may be asymptomatic. Cancer is detected when abnormal digital rectal examination (DRE) results or elevated PSA levels are further investigated. Alternatively, cancer may be detected in tissue obtained during transurethral resection to treat a urinary outflow tract obstruction.
Local symptoms
In the pre-PSA era, patients with prostate cancer commonly presented with local symptoms. Urinary retention occurred in 20-25%, back or leg pain occurred in 20-40%, and hematuria occurred in 10-15%. Currently, with PSA screening, patients report urinary frequency (38%), decreased urine stream (23%), urinary urgency (10%), and hematuria (1.4%). However, none of these complaints is unique to prostate cancer and each could arise from a variety of other ailments. Forty-seven percent of patients are asymptomatic.
Metastatic symptoms
Metastatic symptoms include weight loss and loss of appetite; bone pain, with or without pathologic fracture (because prostate cancer, when metastatic, has a strong predilection for bone); and lower extremity pain and edema from nodal metastasis obstructing venous and lymphatic tributaries. Uremic symptoms can occur from ureteral obstruction caused by local prostate growth or retroperitoneal adenopathy secondary to nodal metastasis.
DRE
An irregular, firm prostate or nodule is typical, but many cancers are found in prostates that feel normal.
PSA screening
PSA screening is currently the single best test for prostate cancer and it is widely used in the diagnosis of prostate cancer, but it does have limitations. These have led to efforts to improve its diagnostic specificity through the use of derivative indices, e.g., PSA density, age-related PSA levels, TZ-PSA density, PSA velocity, free PSA levels, complexed PSA measurements, and free-to-total PSA ratios. This last index measures both bound and free PSA as a percentage of total PSA and is a useful additional discriminator between cancer and benign pathology, particularly in patients with moderately elevated serum PSA levels in the 4- to 10-ng/mL range. The lower the percentage of free PSA, the higher is the likelihood of cancer.
Some studies have shown an increased specificity with this complexed PSA and assay for complexed PSA could conceivably replace total PSA measurements in the future.
Transrectal Ultrasound (TRUS): No optimal imaging technique has been developed for the demonstration of cancer within the prostate. Currently, TRUS offers the best opportunity to demonstrate prostate cancer. However, many prostatic tumors are isoechoic and multifocal, TRUS has major limitations in fully demonstrating these prostate cancers. Furthermore, TRUS has low specificity because many pathologic conditions may demonstrate similar appearances as hypoechoic areas.
Prostatic Biopsy: The original systematic approach for biopsy included the acquisition of 6 cores, 3 cores from each of the lobes of the prostate at the base, mid gland, and apex in a parasagittal plane. Current practice is to obtain an increased number of cores, i.e., lateral PZ cores, mid gland cores, or TZ cores, in addition to the standard 6 cores. A 10-core biopsy incorporating the traditional 6 parasagittal samples and 2 lateral samples from the right and left prostatic lobes is now a standard technique for systematic biopsy.
Systematic biopsy may be supplemented with cores obtained through hypoechoic PZ lesions. Some authors describe a saturation biopsy approach in which as many as 40 cores are obtained under general anesthesia or sedation. The precise biopsy approach must be individually tailored on the basis of the patient’s clinical features (DRE and PSA levels)
X rays: A chest radiograph may be considered in the evaluation of a patient with known prostate cancer to assess chest symptoms, weight loss, localized bone pain, or constitutional symptoms. Skeletal radiographs may show sclerotic metastases or lytic lesions with bone destruction.
Bone Scan: Radionuclide bone scanning after the injection of a technetium-99m tracer is the standard method for assessing potential bone metastases from prostate cancer. With diffuse bone metastases, a so-called superscan may be seen. This superscan demonstrates high uptake throughout the skeleton, with poor or absent renal excretion of the tracer.
CT Scan: CT cannot depict T1 or T2 tumors accurately. T3 tumors may show invasion of periprostatic fat or seminal vesicles.Thus, CT has a limited role in assessing prostatic cancer, but it may be helpful in detecting nodal involvement.
MRI: MRI is better for evaluation of patients with prostate cancer because it can be used to assess primary disease in the prostate and involvement of the local lymph nodes.
As with TRUS, MRI cannot accurately depict cancer in the TZ. The current role of MRI is in the assessment of local extracapsular extension and invasion of the seminal vesicle.
In research studies, endorectal MRI was more accurate than body-coil MRI in the local staging of the primary tumor. Dynamic endorectal MRI with gadolinium enhancement may provide optimal visualization of cancer in the prostate, but even this may cause significant under staging in approximately 30% of prostate cancers.
Magnetic resonance spectroscopy performed by using citrate and choline can provide specific information regarding prostatic metabolism. These data may be useful in assessing the biological potential of the primary tumor and the extracapsular extension of the tumor.
MR Lymphography: A new technique to detect clinically occult lymph node metastases is “MR lymphography” using a highly lymphotropic MR contrast agent. Small lymph node metastases were identified with higher sensitivity than with conventional MR scanning; this potentially valuable test needs further evaluation.
PET Scan: Positron emission tomography (PET) with 18-fluoro-2-deoxyglucose (FDG) may have a role in the detection of lymph node metastases from prostate cancer, particularly in patients with relapsed disease after primary treatment. Localized disease within the prostate and pelvic lymph nodes can be difficult to image because of the proximity of activity of the bladder. The sensitivity of FDG PET for detection of recurrence after radical prostatectomy currently is less than 50%.
Immunoscintigraphy: The use of immunoscintigraphy to assess prostate cancer is under investigation. With this method, radiotracer-labeled antibodies to acid phosphatase and PSA are used. Initial studies used iodine-131–labeled antiprostatic acid phosphatase antibody, and subsequent studies have used indium-111–labeled antibody. The use of labeled anti–carcinoembryonic antigen antibodies is being investigated.
Future perspectives
Currently, research studies are underway to investigate whether sonographic contrast agents have a role in the identification of cancer in the prostate.
Research studies are also being conducted to assess the value of elastography in the diagnosis of prostate cancer; however, the role of this technique is still unclear.
Molecular prognostic markers
Over the past few years, several molecular markers have been shown to aid in the prognostication of patients undergoing treatment for localized and metastatic prostate cancers. Assessment of the molecular alterations or gene products of TP53, RB, BCL2, cathepsin-D, CDH1, and PTEN, among many others, have been reported. Prospective trials are needed to assess these markers more thoroughly before their implementation in current management is recommended.
Reverse transcriptase-polymerase chain reaction
Reverse transcriptase-polymerase chain reaction (RTPCR) testing may be able to find very small amounts of PSA nucleic acid in the blood stream, prostatic fossa, or bone marrow. In the future, this may be helpful in determining which patients have residual tumor following surgery (RTPCR-positive prostate fossa) or a higher rate of tumor recurrence (RTPCR-positive lymph nodes at surgery or persistently positive bone marrow samples months after treatment).
Staging
The 2002 TNM staging system is used to stage prostate cancer, as follows:
T - Primary tumor
TX - Primary tumor cannot be assessed
T0 - No evidence of primary tumor
T1 - Clinically in apparent tumor not palpable or visible by imaging
T1a - Tumor incidental histologic finding in less than or equal to 5% of tissue resected
T1b - Tumor incidental histologic finding in greater than 5% of tissue resected
T1c - Tumor identified by needle biopsy (because of elevated PSA level); tumors found in 1 or both lobes by needle biopsy but not palpable or reliably visible by imaging
T2 - Tumor confined within prostate
T2a - Tumor involving less than half a lobe
T2b - Tumor involving less than or equal to 1 lobe
T2c - Tumor involving both lobes
T3 - Tumor extending through the prostatic capsule; no invasion into the prostatic apex or into, but not beyond, the prostatic capsule
T3a - Extracapsular extension (unilateral or bilateral)
T3b - Tumor invading seminal vesicle(s)
T4 - Tumor fixed or invading adjacent structures other than seminal vesicles (e.g., bladder neck, external sphincter, rectum, levator muscles, pelvic wall)
NX - Regional lymph nodes (cannot be assessed)
N0 - No regional lymph node metastasis
N1 - Metastasis in regional lymph node or nodes
Regional lymph nodes are assessed by surgical removal or biopsy of the pelvic lymph nodes, including the obturator chain. The surgical boundaries are the bifurcation of the common iliac, the obturator nerve, and the node of Cloquet.
Distant metastasis
PM1c - More than 1 site of metastasis present
MX - Distant metastasis cannot be assessed
M0 - No distant metastasis
M1 - Distant metastasis
M1a - Nonregional lymph node(s)
M1b - Bone(s)
M1c - Other site(s)
Treatment
Standard treatments for localized prostate cancer include surgery, radiation therapy (external beam or brachytherapy with and without androgen ablation), or observation.
Early localized disease (clinical stage T1-2N0M0)
Surgical therapy
The goal is disease-free survival if the cancer is localized and is symptom-free survival if the cancer has spread outside the confines of the prostatic capsule.
Radical Prostatectomy: is removal of the prostate and seminal vesicles. Pelvic lymphadenectomy includes the medial half of the external iliac and obturator fossa from the bifurcation of the internal and external iliacs to the node of Cloquet. Currently, 3 approaches are used to remove the prostate gland.
1. Radical retropubic prostatectomy: This can be performed using either an open or laparoscopic technique. The laparoscopic technique can be performed with robotic assistance.
2. Radical perineal prostatectomy: Advantages include less discomfort, more rapid return of bowel function, and shorter hospitalization. Disadvantages include specialized instruments, lack of node sampling or node sampling performed on a separate date, and, in some studies, higher fecal incontinence rates.
3. Nonrobotic laparoscopic prostatectomy: early data on intraoperative and postoperative complications appear to be similar to those of open prostatectomy.
Although the follow-up was short (<5 y), cancer control appeared equal to that of the open procedure. However, regardless of the approach, the many exceptions and treatment choices must be individualized to each patient’s specific situation.
Complications may include impotence, urinary incontinence, strictures, and, possibly, fecal incontinence. Potency rates in previously potent patients vary greatly (5-80%) and depend on patient age and whether a nerve-sparing surgery (unilateral or bilateral) is performed or whether a non–nerve-sparing surgery is performed. Incontinence (4-30%) also depends on the patient’s age and whether the surgery is nerve sparing or non–nerve sparing. Strictures (10%) and, rarely, fecal incontinence occur; the latter may occur more commonly with perineal prostatectomy.
Nonsurgical therapy (Clinical Stage T1-T2 N0M0)
Watchful waiting
Watchful waiting, a program of regular examinations, PSA monitoring, and DREs, is considered in patients of advanced age or those who have significant life-limiting comorbidities and a life expectancy of less than 15 years. Recent evidence supports these recommendations, and further evidence suggests that patients on watchful waiting for more than 15 years sustain significant disease progression.
Androgen ablation
Androgen ablation has been used in situations in which patients are unwilling to undergo potentially curative treatment options yet want some form of treatment beyond watchful waiting.
Androgen ablation can be performed in multiple ways, such as surgical orchidectomy, via luteinizing hormone–releasing hormone agonists, luteinizing hormone–releasing hormone antagonists, or oral antiandrogens (steroidal and nonsteroidal).
External beam radiation therapy
This is used with curative intent for patients with clinically localized cancer and is often combined with androgen ablation.
Several Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer trials have determined that androgen ablation, when combined with external radiation, yields improved disease-specific survival and increased time to recurrence in patients with locally advanced or high-grade prostate cancer. The advantage of this approach in patients with early disease remains to be determined, but it could offer significant advantages when used in younger patients with significant longevity (>20 y). Complications of external radiotherapy include cystitis, proctitis, enteritis, impotence, urinary retention, and incontinence (7-10%).
Brachytherapy
Types of brachytherapy include low–dose rate brachytherapy and high–dose rate brachytherapy. Either type may be used alone or in combination with external beam radiotherapy, depending on the PSA level and the cancer grade.
Complications of brachytherapy are generally similar to those of conformal or intensity-modulated external radiotherapy.
Transperineal cryotherapy
The mechanism of cell death due to cryotherapy involves 3 processes, direct mechanical shock, osmotic shock, and cellular hypoxia.
By using third generation argon gas–driven probes, the freezing process can be turned on and off very rapidly, allowing precise extension of the ice ball.
Disease-specific survival for early-localized disease at 10 years
The ranges of the disease-free 10-year survival rates for early-localized disease listed below are wide because the outcomes of these treatments vary as a function of tumor aggressiveness (i.e., based on Gleason score and PSA level). In addition, significant differences exist among series from various institutions.
Radical prostatectomy (80-95%)
Brachytherapy and external radiation (80-95%)
Watchful waiting (50-73%)
Locally advanced disease (T3-4N0M0)
Radical Prostatectomy
Radical prostatectomy is only occasionally indicated for patients who have undergone a high level of selection and long-term neoadjuvant androgen ablation. The benefit of long-term (i.e., >6 mo) neoadjuvant androgen ablation prior to surgery is currently being studied in clinical trials.
Follow up
DRE has not been shown to offer any added advantage in the detection of local recurrence beyond PSA testing; hence, it is not routinely performed.
PSA testing is performed every 3-4 months for the first 2 years, every 6 months for the third and fourth year and yearly thereafter
Non-Surgical therapy (T3-T4N0M0)
Watchful waiting: 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.
Androgen Ablation
External beam radiotherapy
If brachytherapy is used, it is often combined with external beam and hormonal therapy.
Follow-up after radiotherapy
Watchful waiting and androgen ablation
A DRE and PSA test are performed every 3-12 months.
Although not unanimous, many experts believe that treating patients for metastatic disease with androgen ablation before they become symptomatic offers the potential for increased survival. Hence, bone scans are performed yearly in many patients. An alternative approach has been to perform yearly bone scans once the serum PSA level exceeds 40 ng/ml, which is associated with a significant probability of positive bone scan results.
Some have recommended biopsy of the prostate at 18-24 months to determine if a change has occurred in the grade of the cancer. If such a grade change occurs, some physicians and patients may consider more definitive therapy.
Disease-specific survival for advanced localized disease at 10 years
The disease-specific 10-year survival rate for advanced localized disease in patients treated with brachytherapy and external radiation is 40-62%. Holmberg et al found improved disease-specific survival in patients treated with surgery compared with watchful waiting (4.6% vs. 8.9%).
Biochemical Recurrence / failure
A biochemical recurrence (i.e., measurable PSA) is considered to have occurred following radical prostatectomy if the PSA level is >0.2 ng/ml or greater than the minimal detectable level of the assay. For example, using the ultrasensitive PSA assays, a cutoff of 0.01 ng/ml or 0.05 ng/ml can be used.
The definition of a biochemical recurrence following radiation is more complex, and significant debate still surrounds this topic. Three options for determining biochemical recurrence include (1) 2-3 consecutive rises in the PSA level following a nadir; (2) 3 consecutive rises in the PSA level regardless of the nadir; and (3) an absolute cutoff of 0.2, 0.5, or 1 ng/ml.
Biochemical recurrence should prompt closer follow-up and consideration of alternate therapies. When the PSA level begins doubling every 10-12 months or reaches a level of 20 ng/dl, imaging studies may be performed.
Bone scan
Chest x-ray film
CT scan of the abdomen and pelvis
Potentially, Tran rectal ultrasound–guided rebiopsy of the prostate or prostatic fossa in patients treated with radical prostatectomy
ProstaScint scan (Cytogen; Princeton, NJ), i.e., capromab pendetide scan: The basis for this nuclear scan is prostate-specific membrane antigen, a glycoprotein restricted to the prostate that is elevated in men with prostate cancer. Prostate-specific membrane antigen is conjugated to the CYT-356 antibody and is used in immunoscintigraphy. This antibody is labeled with indium In 111 and is used to detect extraprostatic spread. Most commonly, it is used in patients who have biochemical recurrence but are candidates for additional external beam radiotherapy. The ProstaScint scan is especially useful for identifying localized recurrence and lymphatic spread
Treatment of Biochemical failure
The decision to start treatment on patients with biochemical failure is controversial. However, therapeutic options may include the following:
LHRH agonists alone
Combined androgen blockade: This involves an LHRH agonist plus an oral anti androgen.
Monotherapy using bicalutamide: A dose of 150 mg/d PO currently is being studied.
Gonadotropin-releasing hormone (GnRH) antagonist
Intermittent androgen suppression: The role of androgen withdrawal is well established in the treatment of patients with advanced prostate cancer. Indications for androgen withdrawal therapy include newly diagnosed metastatic disease, localized disease with high risk of systemic relapse, PSA rise during treatment, and biochemical failure after local therapy.
Prostate cancer is amenable to control by intermittent androgen suppression, affording these patients improved quality of life during time off therapy, with reduced toxicity and costs. Studies are being conducted to determine effects on patient outcome and survival.
Combination therapy with finasteride and flutamide: This treatment currently is being studied in an effort to improve the quality of life and to reduce disease progression.
Patients who have PSA (biochemical) failure following radical prostatectomy and have no evidence of metastatic disease have the options of watchful waiting, radiotherapy, or hormonal ablation as salvage therapy. The choice of therapy depends on the timing of the recurrence (i.e., soon after surgery) and the rate of PSA level elevation.
Similarly, patients who have PSA failure following radiation therapy have the options of watchful waiting, brachytherapy, prostatectomy, cystoprostatectomy, cryotherapy, and hormonal ablation.
Locally advanced prostate cancer (T3-T4 or N1)
Standard treatment for patients with locally advanced or locoregional prostate cancer (stage T3-T4 or N1) is nonsurgical and includes palliative local radiation or primary hormone therapy.
Data from randomized trials indicate that primary radiation therapy results in a PSA-free survival rate of 15-20% and an objective disease-free survival rate of less than 50%, with an overall survival rate of approximately 60% at 5 years. To improve outcome of therapy in these groups of patients, adjuvant or neoadjuvant androgen deprivation has been evaluated in 3 randomized trials, 2 by the Radiation Therapy Oncology Group (RTOG) and one by the EORTC.
Metastatic disease
In metastatic disease, palliative therapy has produced a median progression-free survival of 18-20 months and an overall survival of 24-36 months. However, virtually all patients develop hormone-refractory disease.
Management of metastatic prostate cancer is similar to that of locally advanced prostate cancer, except that palliative radiation should be instituted at painful metastatic sites and to the bony lesions with impending fractures. These lesions also may need orthopedic stabilization.
Flare with LHRH agonists is more common in this group of patients; therefore, pretreatment with antiandrogens is necessary.
Treatment-related hypercalcemia might result from eradication of bony metastasis and can require emergency management.
Other supportive measures include treatment of anemia and bleeding, management of disseminated intravascular coagulation (if it occurs), opioids for pain control, ureteral stenting or diversion for ureteral obstruction, and management of osteoporosis using bisphosphonates and adjuvant therapy.
Early versus delayed treatment for metastatic disease
In recent years, the old controversy of appropriate timing of androgen deprivation therapy has gained new and stronger popularity due to the advent of less toxic and well tolerated pharmaceutical agents, such as LHRH agonists and antiandrogens. Laboratory studies have demonstrated that early hormone therapy does not result in earlier resistance.
The Medical Research Council study published in 1997 was a randomized study of 938 patients with locally advanced or asymptomatic metastatic prostate cancer. Patients received either immediate treatment with orchiectomy or LHRH agonist versus the same treatment deferred until symptoms occurred. Development of extraskeletal metastases, pathologic bone fractures, spinal cord compression, and ureteric obstruction was twice as common in the deferred-treatment group. Overall survival was significantly prolonged in the patients who were treated early. Studies by Eastern Cooperative Oncology Group and Eastern Cooperative Oncology Group have shown similar results
Combined androgen blockade (CAB)
Labrie and colleagues described the concept of CAB, in which LHRH accomplished medical castration and antiandrogens achieved peripheral blockade (1995). Initially, they reported improved response and survival rates for patients who received LHRH agonists and antiandrogens.
The benefits of CAB versus LHRH alone remain controversial. Monotherapy with LHRH agonists or antiandrogens unquestionably offers better quality of life as measured by sexual function, fewer hot flashes, and other parameters.
Two other major randomized studies have documented clear benefits of CAB. But , the most recent meta-analysis study by the Prostate Cancer Trialists’ Collaborative Group included 22 trials with a total of 5710 patients have shown no statistically significant survival advantage exists for CAB.
Management of hormone-refractory prostate cancer
In patients with castrate serum testosterone levels, hormone-refractory prostate cancer is defined as demonstration of 2-3 consecutive PSA rises, obtained no less than 2 weeks apart, and/or documented disease progression based on findings from computed tomography (CT) and/or bone scan, bone pain, or obstructive symptoms.
Unfortunately, all patients with metastatic disease eventually become resistant to androgen ablation and most ultimately will die from the disease. The median time to symptomatic progression after a rise in PSA level of more than 4 ng/ml is approximately 6-8 months, and the median time to death is 12-18 months. Once the patients exhibit symptoms, the median survival is less than 1 year.
Unfortunately, therapeutic options for patients with hormone-refractory prostate cancer are very limited, and no definite long-term survival benefits currently have been demonstrated by any systemic therapy.
Short-term palliative response and improved quality of life in patients with hormone-refractory prostate cancer is achieved presently by single or multimodal therapies, which may include second-line hormone manipulations, megestrol, addition of antiandrogens, corticosteroids, ketoconazole, radiation therapy, chemotherapeutic agents, mitoxantrone, estramustine, taxanes, bisphosphonates, suramin, chemohormonal therapy, and some investigational modalities (e.g., gene therapy; vaccine therapy; antiangiogenesis drugs such as thalidomide, telomerase inhibitors, matrix metalloproteinase inhibitors, and signal transduction inhibitors).
Hormonal manipulation For Hormone Refractory Prostate Cancer
Oral antiandrogen withdrawal: One of the best options available for patients with hormone-refractory prostate cancer is oral antiandrogen withdrawal. Response to antiandrogen withdrawal occurs in 15-30% of cases. The range of response duration is observed to be 1-12 months or more (median 3.5 mo). Both PSA declines and clinical responses have been observed. PSA decline is not observed until 2-6 weeks after androgen withdrawal. The beneficial effect in this phenomenon is postulated to be due to the ability of androgen-dependent cells to resurge and inhibit the growth of the androgen-independent cell population.
When antiandrogen therapy is restarted following a secondary rise in the PSA level after a time, a PSA decline may be noticed again. Note that in certain patients, flare of pain and progression of disease may be observed when antiandrogens are withdrawn,. Continuing LHRH agonists in these patients to achieve survival benefits remains controversial.
Antiandrogen addition: If patients are receiving an LHRH agonist alone, PSA response of more than 50% and other subjective responses have been observed in 15-80% of the patients when an antiandrogen is added. The median duration of response is only 4 months. Survival benefits are unclear.
Bisphosphonates: Bisphosphonates, which are stable analogs of calcium pyrophosphate, inhibit osteoclastic activity in bone, relieving bone pain. In addition, they also may have a beneficial effect on the progression of prostate cancer.
Zoledronic acid (Zometa) has shown some promising results.
Radiation therapy: External beam radiation therapy is used to palliate painful isolated bone metastasis in patients with hormone-refractory prostate cancer and in patients with impending spinal cord compression.
Certain radiopharmaceutical agents, such as strontium chloride 89 and samarium 153, relieve pain by delivering beta ray irradiation at new bone formation sites.
Suramin:Suramin acts via growth factor inhibition. Suramin is an active drug in patients with hormone-refractory prostate cancer and can be used in combination with other agents.
Chemohormonal therapy: No active well-tolerated cytotoxic agent has been identified that has shown significant survival advantage without affecting quality of life.
Gene therapy
Treatment options may include corrective gene therapy (i.e., replacing a normal tumor suppressor gene in tumors with a mutated one) or toxic gene therapy to destroy cancer cells. Clinical trials using prostate-specific adenovirus, which expresses a gene toxic to prostate cancer cells, currently are underway in several centers worldwide. Other options include tumor vaccines or vaccination with tumor- or prostate-specific proteins such as PSA.