eMedicine Specialties > Urology > Cancer, Prostate

Prostate Cancer - Metastatic and Advanced Disease

Martha K Terris, MD, FACS, Professor, Department of Surgery, Medical College of Georgia
Audrey Rhee, MD, Resident, Department of Urology, Medical College of Georgia; Shaukat M Qureshi, MBBS, FACS, Consulting Staff in Urology, Department of Surgery, Memorial Hospital of Salem County; Clinical Instructor, Department of Urology, Thomas Jefferson University Hospital

Updated: Jun 4, 2009

Introduction

Background

Prostate cancer is the second leading cause of cancer-related death in the United States among men and is the most commonly diagnosed cancer in American males. Most prostate cancer–related deaths are due to advanced disease. Continuous advances have provided a new understanding of the diagnosis, staging, and treatment of metastatic and advanced prostate cancer. The earlier definition of advanced disease (bone metastasis and soft-tissue involvement) has been improved in recent years. This article provides an overview of the current modalities available in the treatment of advanced prostate cancer, highlighting the following points:

• Identification of the population at risk of developing advanced prostate cancer
• Evolution of clinical staging and therapeutic options currently available to these patients
• Controversies surrounding early versus delayed treatment and combined androgen blockade (CAB)
• Definition and management of biochemical failure
• Hormone-refractory prostate cancer

Pathophysiology

Advanced prostate cancer results from any combination of lymphatic, blood, or contiguous local spread.

Frequency

United States

An estimated 1 in 10 men will develop prostate cancer in their lifetime, with the likelihood increasing with age. Since the advent of prostate-specific antigen (PSA) screening, prostate cancer is being detected and treated earlier; however, approximately 10%-20% of newly diagnosed prostate cancer cases involve locally advanced disease. It is comparably less common because more early-stage cancer is currently being discovered. Accumulating evidence is showing that, owing to early diagnosis and treatment, the mortality rate associated with prostate cancer has declined since the 1970s.

Despite the apparent survival advantage of early diagnosis conferred by PSA screening, a recent U.S. Preventive Services Task Force statement recommends against screening for prostate cancer in men aged 75 years or older. The statement also concludes that, currently, the balance of benefits versus drawbacks of prostate cancer screening in men younger than age 75 years cannot be assessed because of insufficient evidence.¹

Because of its genetic linkage, prostate cancer is more common in males with a strong family history of prostate cancer. Likewise, people who smoke, African American males, and patients who consume a diet high in animal fat or high in chromium are at an increased risk.

International

The mortality rate associated with prostate cancer continues to increase in countries such as Australia, Europe, Japan, and Russia.

Mortality/Morbidity

Prostate cancer is the second leading cause of cancer death in the United States among men and is the most commonly diagnosed cancer in American males.

Race

Prostate cancer is more common in African American males, in whom it tends to be more aggressive and progressive, leading to advanced disease. Furthermore, Fowler et al also demonstrated clearly that African Americans tend to have higher-grade carcinoma at diagnosis.²

Age

The incidence of prostate cancer increases with age.

Clinical

History

• Advanced prostate cancer results from any combination of lymphatic, blood, or contiguous local spread.
• Manifestations of metastatic and advanced prostate cancer may include anemia, bone marrow suppression, weight loss, pathologic fractures, spinal cord compression, pain, hematuria, ureteral and/or bladder outlet obstruction, urinary retention, chronic renal failure, urinary incontinence, and symptoms related to bony or soft-tissue metastases.
• Treatment-related symptoms, such as rectal bleeding, gross hematuria, and urethrorectal fistula, which are sometimes associated with radiation therapy, should also be kept in mind.

Physical

• Obliteration of the lateral sulcus or seminal vesical involvement found during rectal examination often indicates locally advanced disease.
• Physical examination findings of adenopathy, lower-extremity edema, and bony tenderness may indicate metastatic disease.
• Neurological examination, including determination of external anal sphincter tone, should be performed to help detect possible spinal cord compression.

Causes

• The most important and established prognosticators for prostate carcinoma include the Gleason grade, the extent of tumor volume, and the presence of capsular penetration or margin positivity at the time of prostatectomy.
  • High-grade prostate cancer, particularly the percent presence of Gleason grades 4 and 5, is associated with adverse pathologic findings and disease progression.
  • Conversely, low-grade prostate tumors can also be biologically aggressive.

Differential Diagnoses

Other Problems to Be Considered

In most cases, the differential diagnoses of advanced prostate cancer do not present any difficulty; however, certain caveats must be considered, as follows:

• Radiologic findings of bony metastases can mimic Paget disease of the bone. Although bony metastases are blastic in nature, lytic lesions can occur, resulting in pathologic fractures. Osteoporotic fractures due to prolonged luteinizing hormone-releasing hormone (LHRH) therapy must be distinguished from pathologic fractures.
• Neurological manifestations should be underscored, and elderly patients with a history of prostate cancer who present to the emergency department with sudden onset of weakness of the legs should raise the suspicion of spinal cord compression, necessitating emergency treatment (spinal cord decompression).
• Similarly, although brain metastases with associated neurological manifestations are rare, they do occur with enough frequency to deserve recognition.
• Lymphomas can manifest as pelvic masses and bone lesions. Coexistence of lymphomas with prostate cancer has also been reported.
• Transitional cell carcinoma and sarcoma of the prostate are more common in men who have undergone prior pelvic radiotherapy for prostate cancer than in men who have not. Likewise, squamous cell carcinoma of the prostate may be observed in men treated with hormonal therapy. All of these can present as a large pelvic mass with or without metastases.

Workup

Laboratory Studies

• Hematological workup should include a CBC count and a chemistry profile, including serum creatinine, liver function tests, serum PSA, free-to-total PSA ratio, and acid and alkaline phosphatase. Any demonstration of abnormalities by these tests may warrant additional studies.
• Urinalysis should be performed. If results are abnormal, ie, indicating the presence of an infection, urinalysis should be followed by a urine culture, especially if the patient is symptomatic.
• Certain molecular markers, such as E-cadherin, p53 and p21, DNA ploidy analysis, human kallikrein 2, and microvessel density (histologic marker of tumor angiogenesis) are also being evaluated to help characterize disease progression.
• Note that not all patients with a relatively high-grade prostate cancer have elevated PSA levels, nor do elevated PSA levels always signify disease progression.

Imaging Studies

• Bone scan: At initial presentation with prostate cancer, the value of a bone scan is limited in patients with a Gleason score of less than 7 and a PSA level of less than 20 ng/mL. Those with a Gleason grade of greater than 6 may be candidates for a bone scan, irrespective of their PSA level. A bone scan may be performed as a baseline for treatment response in patients with recurrent metastatic disease at high risk of having bony metastatic disease. Regardless of these guidelines, a bone scan is indicated in patients with prostate cancer who have symptoms suggesting bony metastases. Activity in the bone scan may not be observed until 5 years after micrometastasis has occurred; therefore, negative bone scan results do not rule out metastasis. In biochemical failure, a follow-up bone scan usually has no value until the PSA level exceeds 30 ng/mL.
• Chest radiography can be used as a baseline study or to help reveal rare pulmonary metastases in select cases.
• Abdominal or pelvic CT scanning or MRI may reveal extracapsular extension, seminal vesical involvement, pelvic lymph node enlargement, liver metastases, and hydronephrosis (due to result of distal ureteral obstruction) in patients suspected to have locally advanced disease. Because the PSA level does not always correlate with disease progression, repeat CT scans or MRIs can help determine treatment response.
• ProstaScint scan: Immunoscintigraphy is used to reveal extraprostatic disease (ie, localized recurrence or lymphatic spread). ProstaScint scans frequently yield false-negative results, but the specificity of the study may be improved when combined with single-photon emission CT (SPECT) imaging or CT scanning.

Procedures

• Transrectal ultrasound-guided needle biopsy of the prostate is indicated for tissue diagnosis in patients who present with elevated PSA levels or abnormal digital rectal examination findings. It should be repeated, if indicated, to determine local recurrence. (For related information, see the article Techniques of Local Anesthesia for Prostate Procedures and Biopsies in eMedicine’s Urology volume.)

Histologic Findings

The Gleason grading system is the most common classification used today that helps determine the histological characteristics of prostate cancer. A grade of 1-5 is assigned to the glandular architecture of the tumor. The sum of the most predominant grade and the second most common histologic pattern determines the Gleason score. Patients with a Gleason score of 6 or higher are likely to progress to advanced cancer (if they have not already done so), as are patients with a PSA value of 10 ng/mL or higher.

Staging

The Whitmore-Jewett classification of stages A-D is no longer widely used. Prostate cancer does not necessarily progress in a sequential manner.

• Currently, the accepted international tumor, node, metastasis (TNM) staging system pertaining to prostate cancer includes the extent of local disease (T), status of regional lymph nodes (N), and distant metastasis (M).
  • Stage T1-2c - Organ-confined disease
  • Stage T3a - Extracapsular extension of the tumor
  • Stage T3b - Invasion of the seminal vesicle(s)
  • Stage T4 - Tumor fixed or tumor invading adjacent structures other than seminal vesicles (eg, bladder neck, external sphincter, rectum, levator muscles, and/or pelvic floor)
  • Stage NX - Regional lymph nodes cannot be assessed
  • Stage N0 - No regional lymph node metastasis
  • Stage N1 - Regional lymph node(s) metastasis
  • Stage MX - Distant metastasis cannot be assessed.
  • Stage M0 - No distant metastasis
  • Stage M1 - Distant metastasis
  • Stage M1a - Distant metastasis other than regional lymph nodes
  • Stage M1b - Metastasis to bone(s)
  • Stage M1c - Other site(s)
  • Stage pM1c - Metastasis to more than 1 site
• The definition of stage D by Whitmore-Jewett has been further stratified by Crawford and Blumenstein.³ The additional stratification is thought to improve classification and understanding of a subset of patients who have hormone-insensitive prostate cancer. The staging is as follows:
  • Stage D1 - Involvement of pelvic lymph nodes
  • Stage D1.5 - Rising PSA level after failure of local therapy (ie, biochemical failure)
  • Stage D2 - Metastatic disease to bone and other organs
  • Stage D2.5 - Rising PSA after nadir level
  • Stage D3 - Hormone-refractory prostate cancer
  • Stage D3.5 - Sensitive to hormones
  • Stage D4 - Insensitive to hormones

Treatment

Medical Care

Discerning whether the patient has widely advanced disease versus locally advanced disease (clinical stage T3) assists in determining what treatment options are available.

Historically, systemic therapy for metastatic and advanced prostate cancer has involved androgen suppression. In metastatic disease, this palliative therapy has yielded 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. Although hormone therapy is associated with significant responses, its curative potential is limited because of the inherent heterogeneity of prostate cancer and the inability of hormones to eradicate all prostate cancer clones, both the androgen-dependent and androgen-independent components.

Despite the steady decline in the incidence of newly diagnosed metastatic prostate cancer and microscopic lymph node metastasis, from 20% in the 1970s to 3.4% in the 1990s, the risk of extraprostatic disease in patients with clinically localized disease remains high, at 30%-60%. Depending on the PSA value, pathologic stage, and histologic grade of the tumor, approximately 50% of patients with clinically localized prostate cancer are estimated to progress despite initial treatment with intent to cure. In some cases of hormone-refractory prostate cancer, the prostate cancer may continue to exhibit hormone dependence. Currently, it is impossible to predict whether these patients may benefit from androgen withdrawal versus continued hormone therapy.

• Radiation treatment
  • For locally advanced prostate cancer (clinical stage T3), the accepted treatment recommendation is external beam radiotherapy (EBRT) as local treatment for cure. Studies have suggested that the addition of androgen deprivation therapy (ADT) yield improvement in progression-free survival in these patients. The standard treatment consists of 2 months of ADT prior and then EBRT throughout. Three-dimensional conformal radiation therapy is available to increase the radiation delivered to the prostate while minimizing the exposure to the rest of the pelvis, namely the bladder and rectum.
  • In patients with metastatic prostate cancer, radiation is also applied for palliative purposes. It is used in patients with hormone-refractory disease with painful bone metastases and in patients with impending spinal cord compression.
  • Adverse effects of EBRT include cystitis, proctitis, enteritis, impotence, urinary retention, and incontinence.
• Biochemical failure/recurrence
  • The most common presentation of advanced prostate cancer is a patient with a rising PSA level in whom initial local therapy has failed.
  • Generally, after a radical prostatectomy, the PSA level should be less than 0.2 ng/mL and, after radiation therapy, less than 0.5 ng/mL. The definition of a rising PSA level is not consistent in the literature, but many agree that 2 consecutive PSA level elevations is considered biochemical failure.
  • Other important prognostic indicators include PSA velocity, time to PSA nadir, time to PSA recurrence, and pattern of PSA recurrence.
  • Pretreatment Gleason score, clinical stage, PSA level, and percentage of positive core biopsy results were recently found to be reliable predictors of failure following local therapy. Unfortunately, no means of identifying recurrences limited to the pelvis is reliable. Although a Gleason grade of 7 or less is associated with a better prognosis than a grade of 8 or more, if the PSA level rise occurs after 2 years following local treatment, the associated survival likelihood is greater than if the rise occurs before 2 years.
  • The decision algorithm for initiation of treatment for biochemical failure is controversial. Certain factors to consider include the type of local therapy previously instituted (if any), the patient's life expectancy, intention and likelihood of cure, risk for increased morbidity, and patient's quality of life.
  • No guidelines have been set for treating patients with advanced prostate cancer in whom local therapy has failed. A balance between disease control and minimization of the toxicity and intolerance of the treatment is difficult to maintain. ADT, while being able to limit disease progression and to reduce urinary outlet obstruction, produces adverse effects and increases the risk of anemia, hot flashes, gastrointestinal tract disturbances, loss of libido, impotence, osteoporosis, muscle wasting, gynecomastia, deep vein thrombosis, congestive heart failure, myocardial infarction, pulmonary edema, and psychological changes. Therapeutic options include the following:
    • LHRH agonists
    • CAB - LHRH agonist with an oral antiandrogen
    • Monotherapy of nonsteroidal antiandrogens (eg, bicalutamide)
    • Gonadotropin-releasing hormone (GnRH) agonist
  • A study by Saad et al (2008) found that the risk of osteopenia, osteoporosis, and bone fractures caused by ADT can be mitigated by appropriate bisphosphonate therapy. The decision to institute bisphosphonate therapy should be based on the risk of these complications on a case-by-case basis. Patients determined to be at risk for such complications should be educated about measured to reduce the risk, including lifestyle modifications that may benefit their general and bone health.⁴
  • Denham et al (2008) reported that the PSA doubling time and the time to biochemical failure can provide useful surrogate endpoints for prostate cancer–specific mortality, potentially meaning that the follow-up period in clinical trials can be significantly reduced. However, further studies are still needed.⁵
  • In a more recent study, based on an evaluation of data from the Radiation Therapy and Oncology Group 92-02 randomized trial, Ray et al (2009) determined that distant metastasis and general failure of clinical treatment at 3 years may be candidates as surrogate endpoints for prostate cancer–specific survival at 10 years, potentially shortening the duration of clinical trials for prostate cancer. However, they concluded that these endpoints still need to be validated in other datasets.⁶
• Androgen deprivation therapy
  • Considered to be the primary approach in the treatment of symptomatic metastatic prostate cancer, ADT has been found to be palliative, not curative. Although it can slightly improve the likelihood of survival, most men progress to hormone-refractory prostate cancer, also termed androgen-independent cancer. These patients have disease progression despite castration levels of ADT.
  • CAB recognizes the 10% contribution of adrenal androgens to the total body testosterone. A GnRH antagonist with a nonsteroidal antiandrogen is used concurrently for what was thought to be complete ADT. However, multiple randomized trials have shown conflicting findings regarding significant improvement in survival.
  • Labrie and colleagues described the concept of CAB, in which LHRH accomplished medical castration and antiandrogens achieved peripheral blockade. Initially, they reported improved response and survival rates.⁷ Additional studies supported these findings.
  • A recent meta-analysis by the Prostate Cancer Trialists' Collaborative Group included 22 trials with a total of 5710 patients with advanced prostate cancer.⁸ Both medical castration and bilateral orchiectomy were included. The overall mortality rate was 56.3% in those receiving CAB versus 58.4% receiving medical or surgical castration alone. Estimated 5-year survival rates were 26.2% with CAB and 22.8% with castration alone. No statistically significant survival advantage was found with CAB. The current American Society of Clinical Oncology (ASCO) guidelines recommend castration alone with either an orchiectomy or GnRH agonist.
  • Intermittent androgen suppression is a well-established treatment offered to patients with advanced prostate cancer; however, it is not considered standard of care. Some indications for androgen withdrawal therapy include newly diagnosed metastatic disease, localized disease with high risk of systemic relapse, PSA level rise during treatment, lack of tolerance for side effects, and biochemical failure after local therapy. Intermittent androgen suppression may delay androgen-independent cancer and increase quality of life (ie, fewer issues regarding potency and libido). Ongoing research is investigating the utility of intermittent treatment.
• Early versus delayed treatment
  • In the years following the introduction of hormone therapy for prostate cancer by Huggins and Hodges,⁹ early institution of such treatment was recommended based on comparison with historical controls.
  • Later, the Veterans Administration Cooperative Urology Research Group (VACURG) studies reversed the recommendation of early hormone therapy; instead, hormone therapy was deferred until symptomatic progression. In addition, prolongation of survival was believed to be secondary to the alteration of the nature of metastatic lesions, thereby creating earlier androgen resistance, rather than a result of early hormone manipulation.
  • In recent years, the old controversy of appropriate ADT timing has gained new and stronger popularity because of 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 confer early resistance. An update of the VACURG study by Byar and Corle determined that disease progression from stage C to stage D was decreased from 50% to 10% with diethylstilbestrol (DES) therapy.¹⁰ Crawford and associates also showed a benefit of early hormone therapy in patients with distant metastases.¹¹
  • 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 treatment with orchiectomy or LHRH agonist, either immediately or after symptoms occurred. Development of extraskeletal metastases, pathologic bone fractures, spinal cord compression, and ureteral obstruction was twice as common in the deferred-treatment group. Overall survival was significantly prolonged in those who were treated early.¹²
  • In a 1999 study by the Eastern Cooperative Oncology Group, 98 patients who underwent radical prostatectomy and were found to have lymph node metastases were randomly assigned to either immediate castration (ie, LHRH agonist/orchiectomy) or therapy instituted at disease progression. The result revealed that immediate therapy significantly improved survival and reduced risk of progression.¹³
• Management of hormone-refractory prostate cancer
  • In patients with castrate serum testosterone levels, hormone-refractory prostate cancer is defined as 2-3 consecutive rises in PSA levels obtained at intervals of greater than 2 weeks and/or documented disease progression based on findings from CT scan and/or bone scan, bone pain, or obstructive voiding symptoms. In a subgroup of patients, the PSA level does not rise at diagnosis or throughout the entire course of the disease.
  • If given enough time, all patients with metastatic disease become resistant to androgen ablation. The median time to symptomatic progression after a rise in PSA level of more than 4 ng/mL is approximately 6-8 months, with a median time to death of 12-18 months. Once the patient exhibits symptoms, the median survival is less than 1 year. No method predicts whether these patients may benefit from androgen withdrawal versus continued hormone therapy.
  • Therapeutic options for patients with hormone-refractory prostate cancer are limited, with lack of evidence for long-term survival. The best outcome for these patients is to maintain or to improve their quality of life.
  • Short-term palliative response and improved quality of life in these patients is achieved presently by single or multimodal therapies, which may include second-line hormonal manipulations, megestrol, addition of antiandrogens, corticosteroids, ketoconazole, radiation therapy, chemotherapeutic agents, mitoxantrone, estramustine, taxanes, bisphosphonates, suramin, chemohormonal therapy, and other investigational approaches.
    • Bisphosphonates: Bisphosphonates, which are stable analogs of calcium pyrophosphate, inhibit osteoclastic activity in bone, relieving bone pain. They may also limit progression of prostate cancer. They are also being studied for the treatment of osteoporosis induced by ADT. Recently, zoledronic acid (Zometa) has shown further promising results.
    • Chemotherapy/chemohormonal therapy: The rationale behind chemohormonal regimens for hormone-naive advanced disease is based on earlier exposure of prostate cancer to cytotoxic chemotherapy, before clonal expansion of androgen independent cells or constitutive expression of cell survival genes becomes established and before patients develop hormone-refractory prostate cancer. In the past, chemotherapy for prostate cancer was found to be ineffectual. Recent developments with antimicrotubule agents and inhibition of tyrosine kinase show promise.
    • Suramin: Suramin acts via growth factor inhibition. It remains active in patients with hormone-refractory cancer and may be used in combination with other agents. Adverse effects include edema, leukopenia, infection, hyperglycemia, anemia, anorexia, dyspnea, platelet abnormalities, elevated creatinine levels, malaise, arrhythmias, and coagulopathy.

Surgical Care

Radical prostatectomy for clinical stage T3 prostate cancer at initial presentation has not historically been considered beneficial because of the increased probability of incomplete resection of the cancer, likelihood of micrometastatic disease, and increased morbidity. A retrospective review of 843 men with stage cT3 prostate cancer who underwent radical prostatectomy at the Mayo Clinic (median follow-up of 10.3 y) reported outcomes that were similar to those with organ-confined disease (stage T2c) during the same period at this institution. Pathologic stage, Gleason grade, positive surgical margin, and nondiploid chromatin were found to be independently associated with increased progression of disease.

• Patients with widely advanced and metastatic prostate cancer were previously treated with androgen deprivation, namely bilateral orchiectomy. Since the introduction of LHRH agonist therapy, surgical intervention has been practiced less often. An indication for immediate bilateral orchiectomy is spinal cord compression.
• Surgical intervention of weight-bearing bones involved in pathologic fractures is mandatory.

Consultations

• Consultation with a radiation oncologist should be obtained for palliative radiation therapy for bone metastases, locally extensive tumors, and on an emergent basis for spinal cord compression.
• Consultations with a neurosurgeon for spinal cord compression and an orthopedic surgeon for pathologic fractures are appropriate.
• Consultation with a medical oncologist may also be considered for chemotherapy.

Diet

• Because a high-fat diet is linked with a higher incidence of prostate cancer, a low-fat diet may be beneficial for patients at high risk of developing prostate cancer (namely those with positive family history, African American males) and for patients undergoing treatment for advanced prostate cancer.
• Tomatoes, broccoli, green tea, soy, lycopenes, licorice root, selenium, and antioxidants have all been hypothesized to be beneficial.
• The Physicians' Health Study II, a long-term randomized controlled trial involving male physicians, recently found that neither vitamin E nor C supplementation reduced the risk of cancer—prostate or otherwise.¹⁴
• Similarly, the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a randomized placebo-controlled trial involving 35,533 relatively healthy study participants from 427 US sites, found that neither selenium nor vitamin E (alone or in combination), at the doses and formulations used, prevented prostate cancer.¹⁵
• For more information, see the article Prostate Cancer - Nutrition.

Activity

• Patients diagnosed with impending paralysis due to spinal cord compression or patients with pathologic fractures should be immediately immobilized until appropriate consultations are obtained.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Gonadotropin-releasing hormone analogs

These agents suppress ovarian and testicular steroidogenesis by decreasing LH and FSH levels.

Leuprolide (Lupron, Viadur, Eligard)

Synthetic nonapeptide analogue of GnRH that acts as potent inhibitor of gonadotropin secretion.
Viadur, a leuprolide implant, provides continuous release of leuprolide for 12 mo. Each implant contains 72 mg leuprolide. The implant is inserted SC in the inner aspect of the upper arm under local anesthesia through a small incision. Must be removed after 12 mo, at which time another implant may be inserted.

Dosing

Adult

Injection: 3.75 mg/mo IM; 11.25 mg IM q3mo or 30 mg q4mo
Implant: 1 implant (65 mg) q12mo; remove implant after 12 mo and insert another one to continue therapy

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity; spinal cord compression

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Urinary tract obstruction, tumor flare, and bone pain may occur; monitor patients for weakness and paresthesias

Goserelin (Zoladex)

Synthetic decapeptide analogue of GnRH, which inhibits pituitary gonadotropin secretion.

Dosing

Adult

3.6 mg/mo SC or 10.8 mg q3mo

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Urinary tract obstruction, tumor flare, hypercalcemia, and bone pain may occur; monitor patients for weakness and paresthesias

Gonadotropin-releasing hormone antagonist

This agent lowers serum testosterone levels by suppressing LH and FSH.

Abarelix (Plenaxis)

Synthetic decapeptide with potent antagonistic activity against naturally occurring GnRHs. Competitively blocks GnRH receptors in pituitary gland. Antagonistic effect suppresses LH and FSH hormones, causing serum testosterone level to decrease, which in turn slows prostate cancer growth. Indicated for advanced prostate cancer in men who cannot take other hormone therapies and who either refuse surgery or are not surgical candidates.

Dosing

Adult

100 mg deep IM (in buttock) on days 1, 15, and 29, then q4wk for total duration of 12 wk

Pediatric

Not established

Interactions

Other drugs that prolong QT interval (eg, quinidine, procainamide, amiodarone, sotalol, dofetilide) may increase risk of severe arrhythmia

Contraindications

Documented hypersensitivity; children, women, or breastfeeding mothers

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Life-threatening immediate-onset systemic allergic reactions may occur following any dose, including first dose (observe patient in office for at least 30 min following administration); following treatment on day 29, monitor serum testosterone level q8wk; increased treatment duration or body weight >225 lb (102 kg) may decrease overall effectiveness; extended treatment may decrease bone mineral density; may cause QT prolongation, hot flushes, sleep disturbance, breast enlargement, or breast/nipple pain; prescribing physicians must be certified following successful completion of a safety program

Bisphosphonates

These are analogs of pyrophosphate that act by binding to hydroxyapatite in bone matrix, thereby inhibiting the dissolution of crystals. They prevent osteoclast attachment to the bone matrix and osteoclast recruitment and viability.

Zoledronic acid (Zometa)

Inhibits bone resorption, possibly by acting on osteoclasts or osteoclast precursors.
May relieve bone pain and may have beneficial effect on progression of prostate cancer.

Dosing

Adult

4-8 mg IV over at least 15 min q3wk for 9-15 mo

Pediatric

Not established

Interactions

Concurrent administration with loop diuretics may increase risk of hypocalcemia

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in renal insufficiency; risk of renal deterioration increased with <15 min IV infusion; flulike syndrome (eg, fever, arthralgias, myalgias, skeletal pain), GI reactions, anemia, insomnia, dyspnea, and electrolyte and mineral disturbances (eg, low serum phosphate, calcium, magnesium, potassium levels) may occur

Antiandrogens

These agents are used as combination agents to treat prostate cancer.

Bicalutamide (Casodex)

Nonsteroidal antiandrogen that competitively inhibits androgen activity by cytosol androgen receptor binding. Monotherapy with 150 mg PO qd is presently being evaluated.

Dosing

Adult

50 mg PO qd as combination therapy

Pediatric

Not established

Interactions

Concurrent therapy with warfarin increases anticoagulation effects (monitor PT times and adjust dose if necessary)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Causes less loss of libido and diarrhea; monitor LFTs; adverse effects include hot flashes, gynecomastia, breast tenderness, and nausea

Nilutamide (Nilandron)

Nonsteroidal antiandrogen that blocks testosterone effects at the androgen-receptor level.

Dosing

Adult

150 mg PO qd

Pediatric

Not established

Interactions

May reduce clearance and increase half-life of vitamin K antagonists, theophylline, or phenytoin, which may increase risk of toxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Adverse effects include severe hepatic impairment, interstitial pneumonitis, visual disturbances, and inability to adapt to darkness

Finasteride (Proscar)

Currently under investigation as combination therapy with flutamide. Inhibits steroid 5alpha-reductase, which converts testosterone into 5alpha-dihydrotestosterone (DHT).

Dosing

Adult

5 mg PO qd

Pediatric

Not established

Interactions

PSA levels decrease as much as 50% in patients with BPH treated with finasteride

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution in liver function abnormalities; adverse effects include decreased volume of ejaculate (does not appear to interfere with sexual function), decreased libido, and impotence

Flutamide (Eulexin)

Nonsteroidal antiandrogen that inhibits androgen uptake or binding of androgen to target tissues.

Dosing

Adult

125 mg (2 cap) PO q8h; not to exceed 750 mg/d

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Patient should not discontinue therapy without physician's advice; causes less loss of libido and diarrhea; monitor LFTs; adverse effects include hot flashes, gynecomastia, breast tenderness, and nausea; photosensitivity may occur with prolonged exposure to sunlight or tanning equipment

Antifungal agents

These agents produce a response similar to that of antiandrogens. They inhibit various cytochrome P-450 enzymes, including 11beta-hydroxylase and 17alpha-hydroxylase, which in turn inhibit steroid synthesis.

Ketoconazole (Nizoral)

Imidazole broad-spectrum antifungal agent that acts on several of the P-450 enzymes, including the first step in cortisol synthesis, cholesterol side-chain cleavage, and conversion of 11-deoxycortisol to cortisol. May inhibit ACTH secretion when used at therapeutic doses.
Causes severe adrenal suppression; therefore, must be used in conjunction with supplementary hydrocortisone.

Dosing

Adult

400 mg PO tid on empty stomach in combination with supplementary hydrocortisone (20 mg in morning and 10 mg in evening)

Pediatric

Not established

Interactions

Isoniazid may decrease bioavailability; coadministration decreases effects of either rifampin or ketoconazole; may increase effect of anticoagulants; may increase toxicity of corticosteroids and cyclosporine (cyclosporine dose can be adjusted); may decrease theophylline levels

Contraindications

Documented hypersensitivity; fungal meningitis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hepatotoxicity may occur; may reversibly decrease corticosteroid serum levels (adverse effects avoided with dose of 200-400 mg/d); administer antacids, anticholinergics, or H2 blockers at least 2 h after taking ketoconazole; adverse effects include GI bloating, nausea, asthenia, and hepatotoxicity

Chemotherapy agents

These agents inhibit cell growth and proliferation. Prostate cancer has been considered essentially a chemoresistant disease because of the poor survival outcomes reported in earlier series. No single agent has resulted in an objective response rate of greater than 30%. Because of the availability of PSA testing to monitor the disease, renewed interest has been generated in this regard, and clinical trials are being conducted.

Docetaxel (Taxotere)

Binds to tubulin and stabilizes the microtubular network, leading to arrest in the G2-M phase of the cell cycle and subsequent programmed cell death. May promote apoptosis in prostate cancer cells, such as inducing Bcl-2 phosphorylation. Found to be 100 times more potent than paclitaxel. Median reported survival in one series was 22.8 mo.

Dosing

Adult

75 mg/m² IV q7-21d

Pediatric

Not established

Interactions

Toxicity may increase when administered concurrently with ketoconazole, erythromycin, or cyclosporine

Contraindications

Documented hypersensitivity to docetaxel or polysorbate 80

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Premedicate with oral corticosteroids (eg, dexamethasone 8 mg bid for 3 d) starting 1 d before docetaxel administration to reduce incidence of hypersensitivity reactions and fluid retention; closely monitor patients with preexisting effusions during first dose of docetaxel for the possibility of exacerbation of the effusion; caution when administering to patients with abnormal liver function; blood counts should be monitored and docetaxel not administered if neutrophil count is <1500/µL; adverse effects include nausea, vomiting, granulocytopenia, GI tract toxicity, fluid retention, anemia, pleural effusions, fatigue, peripheral neuropathy, dyspnea, hyperglycemia, and hyperkalemia

Mitoxantrone (Novantrone)

Inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II.
In 2 randomized phase III trials involving >400 patients, has been shown to induce statistically significant response in controlling pain and improving quality of life, time to treatment failure, and time to disease progression compared with glucocorticoids alone. Generally used in combination with either prednisone or hydrocortisone.

Dosing

Adult

12 mg/m² IV with prednisone 5 mg PO

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in impaired hepatic function and preexisting cardiac disease (cardiotoxicity commonly observed after cumulative dose of 120-160 mg/m²); perform baseline and follow-up cardiac function tests (eg, 2-dimensional echocardiogram and ejection fraction measurements)

Estramustine (Emcyt)

Combines estradiol and nornitrogen mustard. Relatively weak alkylating agent with weak estrogenic activity. Used in combination with vinblastine, etoposide, paclitaxel, docetaxel, mitoxantrone, or corticosteroids to achieve synergistic effects.

Dosing

Adult

280 mg PO tid

Pediatric

Not established

Interactions

Coadministration with milk products or calcium-rich products may impair absorption

Contraindications

Documented hypersensitivity; thrombophlebitis; thromboembolic disorders

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Adverse effects include, nausea, vomiting, edema, gynecomastia, thromboembolic episodes, thrombocytopenia, granulocytopenia, and esophagitis

Paclitaxel (Taxol)

Taxanes alone or in combination with other agents have demonstrated efficacy in the treatment of hormone-refractory prostate cancer. Mechanisms of action are tubulin polymerization and microtubule stabilization.

Dosing

Adult

135 mg/m² IV over 1 h on day 2 of each 21-d treatment cycle; maximum of 6 cycles of therapy have been used in combination with estramustine 280 mg tid and oral etoposide 100 mg/d for 7 d
Alternatively, 120 mg/m² by 96-h IV infusion on days 1-4 of each 21-d cycle with oral EMP 600 mg/m²/d continuously

Pediatric

Not established

Interactions

Coadministration with cisplatin may further increase myelosuppression

Contraindications

Documented hypersensitivity to paclitaxel or polyoxyethylated castor oil; peripheral neuropathy; bone marrow suppression; liver failure; severe cardiac disease

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Premedicate with steroids and H1 and H2 blockers to decrease risk of hypersensitivity reactions; myelosuppression, alopecia, arthralgia/myalgias, and cardiac arrhythmia may occur

Corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli. They are used in combination with agents such as mitoxantrone.

Prednisone (Deltasone, Meticorten, Orasone)

Provides significant subjective palliation and reduces PSA levels. Higher doses may be used in patients with spinal cord compression or cerebral edema.

Dosing

Adult

5 mg PO bid

Pediatric

Not established

Interactions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI ulceration

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur

Hydrocortisone (Hydrocortone, Cortef)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Dosing

Adult

20 mg PO in am and 10 mg PO hs

Pediatric

Not established

Interactions

Clearance may decrease with estrogens; may increase digitalis toxicity secondary to hypokalemia

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular skin infections; GI ulceration

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hyperthyroidism, osteoporosis, peptic ulcer, cirrhosis, nonspecific ulcerative colitis, diabetes, and myasthenia gravis

Follow-up

Further Inpatient Care

• Supportive inpatient care may be required for pain management in terminally ill patients with progressive prostate cancer in whom all measures have failed to elicit response.

Prognosis

• The Partin tables are the best nomogram for predicting prostate cancer spread and prognosis.

Patient Education

• For excellent patient education resources, visit eMedicine's Prostate Health Center and Cancer and Tumors Center. Also, see eMedicine's patient education article Prostate Cancer.

Miscellaneous

Medicolegal Pitfalls

• Impending pathological fractures caused by spinal cord compression due to a flare response or other causes must be promptly recognized and treated to avoid paralysis.
• Family counseling for a terminally ill patient with an anticipated poor outcome is crucial to avoid any unreasonable expectations from arising.
• Any experimental treatment modalities must be clearly outlined, with risks and potential benefits.

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Keywords

advanced prostate cancer, metastatic prostate cancer, prostate-specific antigen, PSA, Gleason score, prostatic cancer, combined androgen blockade, CAB, biochemical failure, hormone-refractory prostate cancer, HRPC, luteinizing hormone-releasing hormone, LHRH, androgenic suppression, antiandrogens, orchiectomy

Contributor Information and Disclosures

Author

Martha K Terris, MD, FACS, Professor, Department of Surgery, Medical College of Georgia
Martha K Terris, MD, FACS is a member of the following medical societies: American Cancer Society, American College of Surgeons, American Institute of Ultrasound in Medicine, American Urological Association, New York Academy of Sciences, and Society of University Urologists
Disclosure: Nothing to disclose.

Coauthor(s)

Audrey Rhee, MD, Resident, Department of Urology, Medical College of Georgia
Disclosure: Nothing to disclose.

Shaukat M Qureshi, MBBS, FACS, Consulting Staff in Urology, Department of Surgery, Memorial Hospital of Salem County; Clinical Instructor, Department of Urology, Thomas Jefferson University Hospital
Shaukat M Qureshi, MBBS, FACS is a member of the following medical societies: American College of Surgeons, American Medical Association, American Urological Association, and Medical Society of New Jersey
Disclosure: Nothing to disclose.

Medical Editor

Bradley Fields Schwartz, DO, FACS, Professor of Urology, Director, Center for Laparoscopy and Endourology, Department of Surgery, Southern Illinois University School of Medicine
Bradley Fields Schwartz, DO, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Association of Military Osteopathic Physicians and Surgeons, Endourological Society, Society of Laparoendoscopic Surgeons, and Society of University Urologists
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Martin I Resnick, MD †, Former Lester Persky Professor and Chair, Department of Urology, Former Professor, Department of Oncology, Case Western Reserve University School of Medicine
Martin I Resnick, MD † is a member of the following medical societies: American College of Surgeons, American Federation for Medical Research, American Institute of Ultrasound in Medicine, American Medical Association, American Society for Bone and Mineral Research, American Society for Reproductive Medicine, American Society of Andrology, American Surgical Association, American Urological Association, Association for Academic Surgery, Endocrine Society, National Kidney Foundation, Ohio Urological Society, and Pan American Medical Association
Disclosure: Nothing to disclose.

CME Editor

J Stuart Wolf Jr, MD, FACS, David A Bloom Professor of Urology, Director of Division of Minimally Invasive Urology, Department of Urology, University of Michigan
J Stuart Wolf Jr, MD, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Catholic Medical Association, Endourological Society, Society for Urology and Engineering, Society of Laparoendoscopic Surgeons, Society of University Urologists, and Society of Urologic Oncology
Disclosure: Terumo Corporation Consulting fee Consulting; Omeros Corporation Consulting fee Consulting

Chief Editor

Edward David Kim, MD, FACS, Professor of Surgery, Division of Urology, University of Tennessee Graduate School of Medicine; Consulting Staff, University of Tennessee Medical Center
Edward David Kim, MD, FACS is a member of the following medical societies: American College of Surgeons, American Society for Reproductive Medicine, American Society of Andrology, American Urological Association, and Tennessee Medical Association
Disclosure: Lilly Consulting fee Consulting; Astellas Consulting fee Speaking and teaching; Indevus Consulting fee Speaking and teaching

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