Metastatic Prostate Cancer
BACKGROUND
What % of newly diagnosed prostate cancer pts present with advanced Dz?
~10%–20% of pts present with advanced Dz (local and/or metastatic).
Has the incidence of metastatic prostate cancer changed with the introduction of the PSA?
Yes. The introduction of the PSA into general practice in the early 1990s appears to have decreased the incidence of metastatic prostate cancer; a SEER database analysis showed a 52% decrease in the incidence of metastatic prostate cancer Dx from 1990–1994. (Stephenson RA et al., World J Urol 1997)
How are most cases of metastatic prostate cancer identified?
The majority of metastatic prostate cancer cases are identified by an isolated biochemical (PSA-only) recurrence; a much smaller % of pts are detected by signs/Sx of metastatic Dz.
In what % of pts with advanced prostate cancer are serum PSA values abnl?
~95% of pts with metastatic Dz also have an abnl PSA, which is the most sensitive and specific marker for recurrence.
What is the anticipated natural Hx of prostate cancer after biochemical failure following local therapy?
Following local therapy and subsequent biochemical failure, the median time to development of mets is 8 yrs, and the median time to death is 13 yrs. (Pound CR et al., JAMA 1999)
What are common predictors of a poorer prognosis after biochemical failure following local therapy?
Poor prognostic factors after biochemical failure following local therapy:
1. Prostate-specific antigen doubling time (PSA-DT) £3 mos
2. Gleason score ≥8
3. T3b Dz
4. LN involvement
(D’Amico AV et al., J Urol 2004; Katz MS et al., JCO 2004; Stephenson RA et al., JAMA 2004; Zhou P et al., JCO 2005)
What are the common sites of mets from prostate cancer?
The most common sites are the bones of the axial skeleton. These lesions are usually osteoblastic but can be lytic as well.
WORKUP/STAGING
What imaging modalities are commonly used for a metastatic workup?
Imaging modalities most commonly used for workup of suspected metastatic prostate cancer include whole body bone scan (technetium-99m bone scintigraphy), CT abdomen/pelvis with contrast, and chest imaging with CXR or CT. X-ray radiographs or MRI should be used if bone scan findings are equivocal.
How accurate are bone scans and CT scans at predicting mets following biochemical failure?
Bone scan and CT scan are rarely positive until PSA values of ≥30 ng/mL are reached in the absence of prior androgen suppression (AS). These scans are also more likely to be positive with higher PSA velocities. (Cher ML et al., J Urol 1998; Kane CJ et al., Urology 2003)
How sensitive and specific is MRI at detecting metastatic Dz?
The role of MRI in this setting has not been thoroughly evaluated. A prospective study of 66 pts with high-risk prostate cancer found the sensitivity/specificity of axial MRI to be 100%/88% compared to bone scan–X-ray sensitivity/specificity of 63%/64% in detecting mets. (Lecouvet FE et al., JCO 2007)
What is ProstaScint?
ProstaScint is indium-111 capromab pendetide, which is a radiolabeled monoclonal antibody used to target prostate-specific membrane antigen. It is FDA approved for detecting localized Dz recurrence after radical prostatectomy but not metastatic Dz. Data are mixed regarding the utility of ProstaScint and it is not commonly included as part of the workup for recurrent prostate cancer.
Is there a role for prostate Bx after biochemical failure in pts initially treated with RT?
Based on an ASTRO consensus statement (1999), re-Bx should be considered if the pt is considering additional local therapy and is >2 yrs s/p completion of RT. (Cox JD et al., JCO 1999)
TREATMENT/PROGNOSIS
What is 1st-line systemic therapy for metastatic prostate cancer?
AS by orchiectomy or, more commonly, the use of a GnRH agonist is considered 1st-line therapy for metastatic prostate cancer.
What is the premise behind androgen deprivation in the Tx of prostate cancer?
Seminal studies by Huggins C et al. revealed that androgen deprivation through castration or estrogen administration leads to the death of prostate cancer cells. (Cancer Res 1941)
Is GnRH agonist therapy superior to orchiectomy for the Tx of metastatic prostate cancer?
Randomized trials and meta-analyses have confirmed equivalent long-term outcomes. Secondary to the irreversibility and psychological morbidity associated with orchiectomy, GnRH agonists are generally considered 1st-line therapy. This therapy has been shown to mainly improve PFS, not OS. (Kaisary AV et al., Br J Urol 1991; Turkes AO et al., J Steroid Biochem 1987; Vogelzang NJ et al., Urology 1995)
What are 3 commonly used GnRH agonists?
Most commonly used GnRH agonists:
1. Goserelin (Zoladex)
2. Leuprolide (Lupron)
3. Triptorelin (Trelstar)
All 3 are available as depot formulations.
What other modalities of AS are utilized?
GnRH antagonists, antiandrogens (AAs; nonsteroidal competitive androgen receptor [AR] antagonists), estrogens, and ketoconazole (antifungal agent, blocks cytochrome P450 enzymes involved in steroidogenesis). The recently approved drug abiraterone works by inhibiting 17-α hydroxylase, an important enzyme in testosterone synthesis. Enzalutamide is a novel AR antagonist that prevents binding of AR to DNA.
Should AS be initiated for biochemical recurrence after definitive RT in the absence of clinically evident mets?
The data are mixed, and the answer is therefore controversial. There are ongoing RCTs designed to address this issue (Early vs. Late Androgen Ablation Therapy [ELAAT], Ontario Clinical Oncology Group [OCOG]). Until these data are available, in our practice, the authors initiate AS in pts with high-risk features (such as Gleason score >7 and rapid PSA-DT). (Faria SL et al., Urology 2006; Walsh PC et al., J Urol 2001)
Should AS be initiated for radiographically evident but asymptomatic mets?
Yes. Studies have shown improved PFS with upfront AS compared with deferring therapy until signs and Sx of clinical progression. (MRC Prostate Cancer Group, Br J Urol 1997; Nair B et al., Cochrane Database Syst Rev 2002)
Is intermittent AS efficacious as continuous AS?
This is uncertain. The premise behind the use of intermittent AS is to help reduce side effects, cost, and progression to hormone-refractory Dz. Phase II studies have validated feasibility and improved QOL, and phase III trials are ongoing with preliminary data and a recent meta-analysis suggesting at least similar outcomes. (Hussain M et al., JCO 2006; Salonen AJ et al., J Urol 2008; Shaw GL et al., BJU Int 2007; Niraula S et al., JCO 2013)
Can AAs be used as monotherapy for AS?
Randomized trial data are mixed. A meta-analysis of several trials showed a trend toward OS benefit with medical/surgical castration compared to nonsteroidal AA therapy. (Seidenfeld J et al., Ann Int Med 2000) As a result, common practice involves both use of GnRH alone or in combination with a nonsteroidal AA.
Should GnRH analogs be used alone or in combination with AAs (combination androgen blockade [CAB])?
Possibly. Several randomized trials and meta-analyses have shown a small but significant OS benefit with CAB. (PCTCG, Lancet 2000; Samson DJ et al., Cancer 2002) GnRH monotherapy may also cause an initial flare of Sx, which can be prevented by preceding therapy with a short course of AAs. (Kuhn JM et al., NEJM 1989) CAB should be recommended if the side effects can be tolerated.
Typically, how long after initiating AS does it take before a pt’s prostate cancer becomes androgen independent?
Androgen independence usually occurs within 2–3 yrs of starting AS. (Eisenberger MA et al., NEJM 1998; Sharifi N et al., BJU Int 2005)
What is the anticipated 5-yr OS for metastatic prostate cancer treated with CAB?
A meta-analysis by the Prostate Cancer Trialists Collaborative Group reported a 25.4% 5-yr OS rate for pts with metastatic prostate cancer treated with CAB. (PCTCG, Lancet 2000)
How are pts with castrate-resistant prostate cancer commonly treated?
If CAB is being administered, withdrawal of the AA may result in PSA decline. If a GnRH analog is being given, switching to AA may help. Additionally, megestrol acetate may be used. Multiple new agents are now available, including abiraterone, enzalutamide, and sipuleucel-T. Palliative focal or systemic radiotherapy may be considered, as appropriate, in conjunction with a bisphosphonate.
What additional therapy should be offered to patients with castrate-resistant prostate cancer and clinically detectable bone metastases?
Denosumab or zoledronic acid, which have been shown in randomized trials to improve bone mineral density and decrease the risk of fracture. (Michaelson MD et al., JCO 2007; Smith MR et al., NEJM 2009)
What are the initial therapy options for patients with newly diagnosed castrate-resistant prostate cancer?
For patients with symptomatic metastases, docetaxel is considered 1st-line therapy. The utility of this regimen was demonstrated in 2 randomized trials: TAX 327 and SWOG 9916. (Tannock IF et al., NEJM 2004; Petrylak DP et al., NEJM 2004) For patients not considered candidates for docetaxel therapy, mitoxantrone, abiraterone, or enzalutamide are all considered acceptable regimens. For patients who are asymptomatic or minimally symptomatic sipuleucel-T (Provenge) is considered an appropriate therapy. Sipuleucel-T, a form of autologous active cellular immunotherapy, was demonstrated to improve OS in a recent phase III randomized trial. (IMPACT trial, Kantoff PW et al., NEJM 2010)
What additional chemotherapy is available to patients who fail initial therapy with docetaxel?
The novel taxane cabazitaxel is considered the preferred 2nd-line agent for patients with symptomatic bone mets from castration-resistant prostate cancer. Cabazitaxel/prednisone has been shown to improve OS in patients who have failed docetaxel in a phase III randomized trial. (de Bono JS et al., Lancet 2010)
What novel radiopharmaceutical is available for patients with symptomatic bone mets from castration-resistant prostate cancer and what is its mechanism of action?
Radium-223 (Xofigo) has recently been approved for use in patients with symptomatic bone mets and no visceral mets. In the recent randomized phase III ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) trial, radium-223 was demonstrated to improve OS and reduced skeletal-related events. (Parker C et al., NEJM 2013) Radium-223 is the first α-particle emitter to be approved for routine clinical practice. The short range and high RBE of the α-particles produced by radium-223 theoretically results in more rapid cell killing and less marrow toxicity compared with previously tested β-emitters such as strontium-89 and samarium-153.
What novel therapies are being considered for metastatic prostate cancer?
Novel therapies considered for metastatic prostate cancer:
1. Gene transfer immunotherapies are designed to express immune-stimulating compounds (e.g., GM-CSF [Gvax] and Prostvac). Phase III data are pending.
2. Gene transfer cytoreduction is designed to express lytic viruses (e.g., CV706/E1a) that preferentially target prostate cancer cells.
3. Monoclonal antibody therapies (e.g., cetuximab, trastuzumab) are being explored in phase I–II studies.
4. Novel tyrosine kinase inhibitors such as cabozantinib (XL184) are being tested in phase III trials.
TOXICITY
What are the common short-term and long-term side effects of AS?
Short-term effects: hot flashes, ↓ libido, fatigue
Long-term effects: gynecomastia, anemia, ↓ muscle mass, ↓ bone density, obesity, mood changes, dyslipidemia, insulin resistance, possibly diabetes and coronary artery Dz
(Higano CS, Urology 2003; Keating NL et al., JCO 2006)
What are common side effects associated with AA therapy, and how long is the Tx course?
Common side effects of bicalutamide, which is the most commonly prescribed AA due to its favorable toxicity profile, include breast tenderness and gynecomastia (50%) as well as loss of libido, diarrhea, and hepatotoxicity. It is generally prescribed for the 1st 2–4 wks with a GnRH analog.
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