AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Prostate cancer is the second leading cause of death in the United States in men dying from cancer and is the most commonly diagnosed cancer in American males. Most of the deaths from prostate cancer are related 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, in which patients presented with 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 risk population of patients who develop advanced disease
• 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

Estimates indicate that 1 in 10 men will develop prostate cancer in their lifetime. The incidence of prostate cancer increases 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. Evidence is accumulating that, owing to early diagnosis and treatment, a decline in prostate cancer-related mortality has occurred since the 1970s.

Because of its genetic linkage, prostate cancer is more frequent in patients 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 have increased risk.

International

Deaths from prostate cancer continue to increase in other parts of the world, such as Australia, Europe, Japan, and Russia.

Mortality/Morbidity

Prostate cancer is the second leading cause of death in the United States in men dying from cancer 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's group also demonstrated clearly that African Americans have higher-grade carcinoma at diagnosis.

Age

The incidence of prostate cancer increases with age.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 relating to bony or soft-tissue metastases.
• Treatment-related symptoms also should be kept in mind, such as rectal bleeding, gross hematuria, and urethrorectal fistula, which sometimes are associated with radiation therapy.

Physical

• Rectal examination findings of obliteration of the lateral sulcus or seminal vesical involvement often indicate 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.
• • The fact that high-grade cancer, particularly the percent presence of Gleason grades 4 and 5, is associated with adverse pathologic findings and disease progression is well recognized.
  • Conversely, low-grade tumors also can be biologically aggressive.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Differential diagnosis of advanced prostate cancer usually does not present any difficulty; however, certain caveats must be considered, as follows:

• Radiologic findings of bony metastases can mimic Paget disease of the bone. Even though 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 presenting in the emergency department with sudden onset of weakness of the legs with a history of prostate cancer should raise the suspicion of spinal cord compression, necessitating emergency treatment (spinal cord decompression).
• Similarly, even though brain metastases with associated neurological manifestations are rare, they do occur with enough frequency to deserve recognition.
• Lymphomas can present as pelvic masses and bone lesions. Coexistence of lymphomas with prostate cancer also has been reported.
• Transitional cell carcinoma and sarcoma of the prostate are more common in men with prior pelvic radiation for prostate cancer compared to men who have not received pelvic radiation therapy. Likewise, squamous cell carcinoma of the prostate can be observed in men treated with hormonal therapy. All of these can present as a large pelvic mass with or without metastases.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab 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. Further studies may be ordered if any of these test results demonstrate abnormalities.
• 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) also are being evaluated to help characterize disease progression.
• Note that elevated PSA levels are not always present in a relatively higher-grade prostate cancer, nor are they always observed in 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 in patients at high risk of having bony metastatic disease as a baseline for treatment response and presence of recurrent 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, a bone scan with negative results does not prove the absence of metastasis. In biochemical failure, follow-up bone scan is usually of no value until the PSA level rises to greater than 30 ng/mL.
• Chest radiography can be used as a baseline study or to help reveal rare pulmonary metastases in select cases.
• Computed axial tomography (CT) scan of the abdomen and pelvis or a magnetic resonance imaging (MRI) study in patients suspected to have locally advanced disease may reveal extracapsular extension, seminal vesical involvement, pelvic lymph node enlargement, liver metastases, and hydronephrosis as a result of distal ureteral obstruction. 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). The false-negative rate associated with ProstaScint scans is high; however, the specificity of the study may be improved when combined with single-photon emission CT (SPECT) imaging or CT scanning.
• 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.

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. 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

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 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. Although hormone therapy is associated with significant responses, its curative potential is limited due to 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, a method to predict whether these patients may benefit from androgen withdrawal versus continued hormone therapy does not exist.
• Radiation treatment
• • For locally advanced disease (clinical stage T3), the accepted recommendation is external beam radiation therapy (EBRT) as local treatment for cure. Studies have suggested the improvement in progression-free survival with the addition of androgen deprivation therapy (ADT) for 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 remaining pelvis, namely the bladder and rectum.
  • For metastatic prostate cancer, radiation is also applied for palliative purposes. It is used for patients with hormone-refractory disease with painful bone metastases and for patients with impending spinal cord compression.
  • Adverse effects related to 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 the patient had previously received (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 side 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
• Androgen deprivation therapy
• • Considered to be the primary approach for treating men with 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 as 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. 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. 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, 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, and, 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 result in early resistance. An update of the VACURG study by Byar determined that disease progression from stage C to stage D was decreased from 50% to 10% with diethylstilbestrol (DES) therapy. Crawford and associates also showed a benefit of early hormone therapy in patients with distant metastases.
  • 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.
  • In a recent study by the Eastern Cooperative Oncology Group, 98 patients who underwent radical prostatectomy (RP) 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.
• 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 rise is neither observed at diagnosis nor 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. A method to predict whether these patients may benefit from androgen withdrawal versus continued hormone therapy does not exist.
  • 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

RP for clinical stage T3 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 RP at the Mayo Clinic with a median follow-up of 10.3 years had outcomes that were similar to those with organ-confined disease of stage T2c during the same period at this institution. Pathologic stage, Gleason's 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.

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

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Drug Category: Gonadotropin-releasing hormone analogs

Suppress ovarian and testicular steroidogenesis by decreasing LH and FSH levels.

Drug Category: Gonadotropin-releasing hormone antagonist

Lowers serum testosterone levels by suppressing LH and FSH.

Drug Category: Bisphosphonates

Analogs of pyrophosphate that act by binding to hydroxyapatite in bone matrix, thereby inhibiting the dissolution of crystals. Prevent osteoclast attachment to the bone matrix and osteoclast recruitment and viability.

Drug Category: Antiandrogens

For use as combination agents to treat prostate cancer.

Drug Category: Antifungal agents

Produce response similar to that of antiandrogens. Inhibit a variety of cytochrome P-450 enzymes, including 11beta-hydroxylase and 17alpha-hydroxylase, which in turn inhibit steroid synthesis.

Drug Category: Chemotherapy 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.

Drug Category: Corticosteroids

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

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Supportive inpatient care may be required for pain management in terminally ill patients with progressive disease 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

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Impending pathological fractures from 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 a poor outcome is crucial to avoid any unreasonable expectations from arising.
• Any experimental treatment modalities must be clearly outlined, with risks and potential benefits.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Aug 24, 2006