Debasish Sundi, MD
Misop Han, MD
BASICS
DESCRIPTION
• Metastatic prostate cancer (CaP) can be nodal disease discovered at prostatectomy or on imaging (N+), or can be distant spread (M+). Most commonly, it affects distant lymph nodes and bone.
• Can be the initial presentation or develop after previous local therapy for CaP, such as radiation therapy or RP.
EPIDEMIOLOGY
Incidence
With PSA screening, the number of men with metastatic disease at 1st presentation has declined over the last 20 yr (∼4%, 2003–2009, SEER data).
Prevalence
Nearly 28,800 men die annually (US) from metastatic disease.
RISK FACTORS
• African American ancestry
• High-fat diet
• Family history
Genetics
None
PATHOPHYSIOLOGY
• CaP arises in prostate glandular epithelium and can spread through the lymphatics or hematogenously.
• Batson plexus are paravertebral veins that extend up from the pelvis to the dural sinuses. This plexus is likely responsible for the high rate of spread of CaP to the vertebral column.
• Testosterone and dihydrotestosterone are the primary regulators of prostate growth.
• 2 sources of androgens in men; testes (95% of total androgens); adrenal glands (remaining 5%).
ASSOCIATED CONDITIONS
Osteoporosis secondary to hormonal therapy
GENERAL PREVENTION
Early androgen blockade for high-risk patients with localized cancer may delay the development of detectable metastatic disease.
DIAGNOSIS
HISTORY
• Urinary symptoms can be indistinguishable from those of BPH and include increased urinary frequency, nocturia, difficulty initiating and maintaining a steady stream of urine, dysuria, and hematuria, and sexual dysfunction.
• The most common symptom of metastatic disease is bone pain, often in vertebrae, pelvis, or ribs.
PHYSICAL EXAM
• DRE may reveal a nodular or enlarged prostate, but the exam may be unremarkable.
• After RP the fossa may be empty or contain palpable recurrent cancer.
• Adenopathy may be detected in the supraclavicular and inguinal lymph nodes.
• Point tenderness elicited on vertebral bodies or rib cage may be indicative of spinal or epidural metastasis.
• CaP metastatic to the spine may result in neurologic symptoms, either from vertebral instability or epidural extension of tumor. Note any leg weakness or urinary and fecal incontinence.
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Serum PSA should be obtained on all patients prior to the start of therapy and is a useful marker of response to therapy.
• Prostatic acid phosphatase is elevated in up to 67% of men with metastatic disease
• Monitor serum testosterone to verify that androgen ablation has testosterone <50 ng/dL
Imaging
• CT of the abdomen and pelvis and bone scan should be performed after initial diagnosis. Bone metastases are typically osteoblastic.
• Evaluate for hydronephrosis secondary to ureteral obstruction.
Diagnostic Procedures/Surgery
Biopsy of prostate or metastatic lesions is required to establish a diagnosis. Identification of visceral metastasis with neuroendocrine features may alter initial management to include initial chemotherapy.
Pathologic Findings
• Adenocarcinoma most common.
• Neuroendocrine carcinoma of the prostate is associated with high Gleason score (9–10), low or undetectable PSA levels, and visceral and lytic bone metastases.
DIFFERENTIAL DIAGNOSIS
• Paget disease; bone metastases from other malignancies
• Adenopathy can be due to lymphoma or other advanced malignancy.
TREATMENT
GENERAL MEASURES
• Androgen blockade for metastatic disease, which is usually considered noncurative.
• Androgen deprivation therapy (ADT) can be administered continuously as well as intermittently (intermittent hormonal therapy or IHT); studies suggest similar survivals when continuous combined androgen blockade (CAB) is compared to intermittent CAB, especially with lower disease burdens.
MEDICATION
First Line
• ADT (1)[B]
– ADT to achieve castrate levels of testosterone, generally considered <50 ng/mL, with some advocating <20 ng/mL (similar to orchiectomy levels)
– Testicular androgen secretion is regulated by the hypothalamus, and the pulsatile secretion of luteinizing hormone releasing hormone (LHRH)
– LHRH agonists (leuprolide, goserelin, triptorelin) interfere with this pulsatile secretion, and after initial flare (testosterone increase) at 7–10 days, achieve medical castration at about 30 days.
– LHRH antagonists (degarelix) rapidly decrease testosterone levels with 44% testosterone castration (<50 ng/dL) at day 1, 96% by day 3. No flare, so useful in situations such as spinal cord compression.
– Antiandrogens (bicalutamide, flutamide, nilutamide) block the LHRH flare reaction initially caused by LHRH agonists and should be used for 7–10 days. Long-term use of antiandrogens + LHRH agonists past the flare period, or CAB is controversial.
– ADT using high-dose bicalutamide (150 mg/d), called antiandrogen monotherapy, is associated with less side effects but may also be a less effective form of ADT and should not be routinely used (not FDA approved in US).
– Initial chemohormonal therapy has recently been reported to extend survival in men presenting with newly diagnosed metastatic prostate cancer (4)
ECOG3805 clinical trial demonstrated a 12 month survival advantage when docetaxel was initially combined with androgen deptivation therapy
Second Line
• Most patients initially benefit from ADT, but the disease usually progresses after 1–4 yr
– Castration-resistant CaP (CRPC): Progression on primary hormonal with a testosterone level of <50 ng/mL, and a rising PSA
– With measurable disease on bone or CT scan of the abdomen and pelvis, the disease is classified as metastatic castration-resistant prostate cancer (mCRPC)
• Secondary hormonal therapy is often utilized for CRPC without metastasis
– If on antiandrogen, the antiandrogen should be discontinued; this will result in a PSA decline in 5–20% of patients
– Addition of an antiandrogen will result in PSA declines of 50% in 15–54% of patients, with median duration of response 4–6 mo
– Ketoconazole blocks testicular and adrenal androgen synthesis; associated with >50% PSA decline in over 50% of patients
– LHRH agonists are continued during therapy to prevent escape from androgen blockade
• Several systemic therapies have demonstrated improved overall survival for metastatic castrate-resistant disease and are discussed in detail in the section on Prostate cancer, rising PSA following androgen ablation (Castratration Resistant Prostate Cancer (CRPC, and mCRPC), Section I.
– Docetaxel, sipuleucel-T, cabazitaxel, abiraterone, enzalutamide, and radium 223
– Mitoxantrone is also an FDA-approved agent for palliation of symptomatic CRPC
– For asymptomatic or minimally symptomatic patients, sipuleucel-T immunotherapy can be used; other agents can be used with more significant symptoms
– In patients with neuroendocrine features, androgen blockade should be initiated along with an immediate chemotherapy regimen incorporating cisplatin/etoposide, carboplatin/etoposide, or a docetaxel-based regimen
SURGERY/OTHER PROCEDURES
• Resection of solitary metastases is not generally performed with curative intent.
• Decompression of epidural metastatic CaP can result in stabilization of the spinal cord and neurologic symptoms. Best results are obtained if the procedure is performed within 24 hr of the onset of symptoms.
• Stabilization of weight-bearing bones (femur and hip) by internal fixation or replacement of the joint prophylactically may prevent fracture.
• In one randomized trial, immediate ADT was associated with improved overall and disease-specific survival among men who had pathologically positive lymph nodes after RP (2)[A]. However, this study was limited by sample size and lack of central pathologic review. In a randomized EORTC study with clinically node-positive disease, early ADT did not have any survival benefit. Because of the gradual natural history of CaP (median survival after development of metastasis after RP = 5 yr (3)[C]) and because the oncologic benefit of early ADT is uncertain, many consider it reasonable to delay ADT until symptoms or measurable disease on imaging are present, to minimize systemic adverse effects of ADT.
ADDITIONAL TREATMENT
Radiation Therapy
• Radiation can be used to palliate solitary painful bony metastases.
• Strontium89 and samarium153 (β-emitters) can palliate bone pain and are most useful for diffuse metastasis.
• Radium-223 (α-emitter) can also be used in the setting of symptomatic bone metastasis
Additional Therapies
• Bone health
– Patients should receive calcium (1,200 mg/d) and vitamin D (800–1,000 IU/d) supplements.
– With ADT, consider zoledronate 4 mg IV yearly, alendronate 70 mg PO weekly, denosumab (RANK ligand inhibitors Prolia 60 mg q6mo SQ for men on ADT or Xgeva with bone mets 120 mg SQ q4wk).
• Metastatic CRPC: Zoledronate 4 mg adjusted to renal function every 3–4 wk IV or denosumab (Xgeva) 120 mg SQ q4wk to prevent skelet al-related events.
Complementary & Alternative Therapies
Weight-bearing exercise and stopping smoking benefits osteoporosis.
ONGOING CARE
PROGNOSIS
• The estimated 5-yr survival of metastatic CaP is 28% (3)[C].
• For patients with lymph node–positive disease post-RP, adjuvant hormone ablation following RP increases overall survival by 2.6 yr vs. RP alone (13.9 vs. 11.3 yr) and reduces mortality risk by ∼46%.
• With metastatic CaP starting androgen blockade, the median time to progression is 18–24 mo. The median survival once patients progress on androgen blockade is 12–19 mo.
COMPLICATIONS
• ADT: Hot flashes, loss of sexual function and libido, loss of muscle mass, decreased in bone mineral density, weight gain, diabetes, lipid profile changes, and neurocognitive dysfunction.
• In a metaanalysis of 8 randomized controlled trials, long-term ADT was not associated with an increased risk of death from cardiovascular causes, however.
• Antiandrogens: Increased liver function test.
• Skelet al-related events: Defined by pathologic fracture, spinal compression/vertebral body collapse, osteonecrosis of the jaw, radiation or surgery to bone, or change in antineoplastic therapy. Androgen blockade can cause osteopenia/osteoporosis; bisphosphonate/RANK ligand therapy can limit reductions in bone mineral density.
– Zoledronic acid: Renal insufficiency, adjust based on creatinine.
– Osteonecrosis of the jaw can result from bisphosphonates and RANK ligand inhibitors; avoid major dental work (extractions) on therapy; perform oral exam before starting.
FOLLOW-UP
Patient Monitoring
• Monitoring patients is controversial. With start of androgen blockade: Check PSA every 3 mo. Confirm castrate testosterone (<50 ng/dL) periodically and upon demonstration of rising PSA while on LHRH therapy.
• At PSA progression, antiandrogen should be withdrawn, and if the patient continues to progress, a CT scan of the abdomen and pelvis should be obtained.
• Timing of PSA testing during chemotherapy is controversial; usually every 3 wk.
• Serum creatinine should be monitored for patients on bisphosphonates. Zoledronic acid should not be given with a Cr >2 mg/dL.
• Monitoring for osteoporosis, obesity, insulin resistance, lipid alteration, and the concern of increased risk of diabetes and cardiovascular diseases in men on ADT should be considered.
Patient Resources
American Cancer Society. http://www.cancer.org/cancer/prostatecancer/index?sitearea=%26dt=10
REFERENCES
1. NCCN Practice Guidelines Version 1.2014. http://www.nccn.org./ Accessed January 6, 2014.
2. Messing, EM, Manola J, Sarosdy M, et al. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med.1999;341:1781–1788.
3. Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999;281(17):1591–1597.
4. NIH-funded study shows increased survival in men with metastatic prostate cancer who receive chemotherapy when starting hormone therapy http://www.cancer.gov/newscenter/newsfromnci/2013/E3805(Posted December 5, 2013).
ADDITIONAL READING
• Antonarakis ES, Eisenberger MA. Expanding treatment options for metastatic prostate cancer. N Engl J Med. 2011;364:2055–2058.
• Hussain M, Tangen CM, Berry DL, et al. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2012;368(14):1314–1325.
• Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596–1605.
• Nguyen PL, Je Y, Schutz FA, et al. Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: A meta-analysis of randomized trials. JAMA. 2011;306(21):2359–2366.
See Also (Topic, Algorithm, Media)
• Antiandrogen Withdrawal Syndrome (Flutamide Withdrawal Syndrome)
• Prostate Cancer, General
• Prostate Cancer, Metastatic (Clinical and Pathologic N+, M+) Images 
• Prostate Cancer, Rising PSA Following Androgen Ablation (Castration-resistant Prostate Cancer,)
• PSA Elevation, General
• Reference Tables: TNM: Prostate Cancer
CODES
ICD9
• 185 Malignant neoplasm of prostate
• 196.5 Secondary and unspecified malignant neoplasm of lymph nodes of inguinal region and lower limb
• 198.5 Secondary malignant neoplasm of bone and bone marrow
ICD10
• C61 Malignant neoplasm of prostate
• C77.4 Sec and unsp malig neoplasm of inguinal and lower limb nodes
• C79.51 Secondary malignant neoplasm of bone
CLINICAL/SURGICAL PEARLS
• ADT is the 1st-line treatment for metastatic CaP.
• There are several antiandrogen and chemo-immunotherapeutic options for men with ADT-refractory metastatic CaP.
• Bone-related issues should be considered in this population.