Metastatic prostate cancer Flashcards
What % of newly diagnosed prostate cancer pts present with locally advanced or metastatic Dz?
Appx 10%–20% of pts will present with at least locally advanced Dz.
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 to 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 proportion of cases are
detected by signs/Sx of metastatic Dz (pain, pathologic fracture, weight loss, anemia, SC compression, etc.). (Lee WR et al., JCO 1997; D’Amico AV et al., JNCI 2003)
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; Freedland SJ et al., JAMA 2005)
What are common predictors of a poorer prognosis after biochemical failure following local therapy?
Poor prognostic factors after biochemical failure following local therapy include: (D’Amico AV et al., JNCI 2003; Stephenson RA et al., JAMA 2004; Zhou P et al., JCO 2005; Horwitz EM et al., IJROBP 2008)
- PSA-DT <3 mos
- GS ≥8
- T3b Dz
- LN involvement
- Short time to biochemical failure following local therapy (<3 yrs)
What is the most common site of prostate cancer mets?
The most common site is the axial skeleton, including the pelvis, vertebral column, ribs, and proximal long bones. Indeed, >80% of pts who die from prostate cancer have bony mets at autopsy. These lesions are usually osteoblastic, but may be lytic as well.
What imaging modalities are commonly used for a metastatic workup?
The 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
a CXR or CT. X-ray radiographs or MRI should be used if bone scan findings are equivocal.
How sensitive are bone scans and CT scans for the detection of mets following biochemical failure?
Bone scan and CT scan are rarely positive until PSA values exceed 30 ng/mL in the absence of prior ADT. These scans are also more likely to be positive with faster PSA velocities. (Cher ML et al., J Urol 1998; Kane CJ et al., Urology 2003)
Is there a role for PET scans in the evaluation of metastatic prostate cancer?
PET imaging is an evolving diagnostic tool, and multiple PET modalities are currently under investigation. Fluciclovine (18F-FACBC) was recently approved by the FDA for the detection of recurrent prostate cancer in men with rising PSA following Sg or RT. Optimal test characteristics are observed at higher PSA values. Multiple prostate specific membrane antigen (PSMA)
targeting PET agents (such as 68Ga-PSMA) are also currently under investigation and may enter routine prostate cancer evaluation in the future.
Is there a role for prostate Bx after biochemical failure in pts initially treated with RT?
Based on an ASTRO consensus statement, prostate re-Bx should be considered if the pt is considering additional local (salvage) therapy and is >2 yrs after the completion of RT. (Cox JD et al., JCO 1999)
What is the standard initial systemic therapy for metastatic prostate cancer?
ADT via surgical bilat orchiectomy, or more commonly through the use of a GnRH agonist, is the standard 1st-line therapy for metastatic prostate cancer. GnRH agonists act on the ant pituitary to cause a reduction in gonadal testosterone production to castrate levels.
What is the pathophysiology of androgen deprivation in the Tx of prostate cancer?
Since the 1940s, testosterone has been implicated in the growth and survival of prostate cancer. Testosterone is converted to the potent dihydrotestosterone (DHT) in target tissues, and DHT binds with high affinity to the AR in prostate cancer cells. Upon translocation to the cancer cell nucleus, DHT-AR binds to DNA androgen response elements, thereby facilitating multiple prostate cancer growth pathways. Therefore, androgen
deprivation can effectively inhibit these growth elements. (Huggins C et al., Cancer Res 1941)
Is GnRH agonist therapy sup to orchiectomy for the Tx of metastatic prostate cancer?
Randomized trials and meta-analyses have confirmed equivalent long-term outcomes. Due to the irreversibility and psychological morbidity associated with surgical orchiectomy, GnRH agonists are generally the preferred
approach for androgen deprivation. This therapy has primarily been shown to improve Dz progression and to reduce Dz-related complications.
What are 3 commonly used GnRH agonists?
- Goserelin (Zoladex)
- Leuprolide (Lupron)
- Triptorelin (Trelstar)
All 3 are available as depot formulations. These different GnRH agonist formulations are considered to be equally efficacious.
What other modalities of androgen suppression are available?
GnRH antagonists (degarelix) achieve fast declines in testosterone to castrate levels and are not associated with a testosterone flare response. Antiandrogens (AAs), which are nonsteroidal competitive androgen receptor (AR) antagonists (including bicalutamide, flutamide, or nilutamide) block the peripheral effects of gonadal and extragonadal (adrenal) androgens. (Klotz L et al., BJU Int 2008)
Should ADT 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. Although the effects on distant metastatic risk remain unclear, available data suggest that
early initiation of ADT may be particularly beneficial for high-risk cancers (GS >7 and rapid PSA-DT). (Faria SL et al., Urology 2006; Walsh PC et al., J Urol 2001)
Should ADT be initiated for radiographically evident but asymptomatic mets?
In general, yes. Although ADT is not curative and primarily administered with palliative intent in the metastatic setting, studies have shown significantly improved PFS and reduced Dz-related complications with early initiation of ADT when c/w therapy deferred until signs and Sx of clinical progression. (MRC Prostate Cancer Group, Br J Urol 1997; Wilt T et al., Cochrane Review 2004)
Is intermittent ADT as efficacious as continuous ADT for metastatic Dz?
No. Continuous ADT is considered the standard of care for treating metastatic Dz. The premise behind the use of intermittent ADT is to potentially help reduce side effects, cost, and progression to castrationresistant
Dz. However; the Intergroup 0162 randomized phase III trial was unable to demonstrate that intermittent therapy was noninf to continuous therapy with respect to survival. However, in men with PSA-only recurrence
following definitive RT, intermittent ADT is noninf to continuous ADT. (Hussain M et al., NEJM 2013; Crook JM et al., NEJM 2012)
Can AAs be used as monotherapy for metastatic Dz?
No. The available evidence does not support the routine use of AA monotherapy for metastatic Dz. Randomized studies demonstrated inf outcomes with standard low-dose bicalutamide when compared to castration
therapy. In addition, a meta-analysis of several trials showed a trend toward OS benefit with medical/surgical castration compared to nonsteroidal AA therapy. As a result, common practice involves use of either a GnRH
agonist alone or in combination with a nonsteroidal AA (and not AA monotherapy). (Bales GT et al., Urology 1996; Kaisary AV et al., Eur Urol 1995; Seidenfeld J et al., Ann Int Med 2000)
Should GnRH analogs be used alone or in combination with AAs (combined androgen blockade [CAB])?
Possibly. Several randomized trials and meta-analyses have shown a small but significant OS benefit with CAB relative to ADT monotherapy. However, the potential benefit of CAB must be balanced with potential increased toxicity in an individual pt. Of note, GnRH monotherapy may cause an initial flare of testosterone and Dz-related Sx, which can be prevented by preceding therapy with a short course of AAs. (PCTCG, Lancet 2000; Samson DJ et al., Cancer 2002; Kuhn JM et al., NEJM 1989)
What is the anticipated median OS for pts with metastatic castration sensitive prostate cancer initiating Tx with ADT?
The median OS in men with metastatic prostate cancer initiating ADT is appx 4–5 yrs, depending on the level of Dz burden. (Hussain M et al., NEJM 2013; Sweeney CJ et al., NEJM 2015; James ND et al., Lancet 2016)
Is there a role for chemo in the Tx of castration-sensitive metastatic prostate cancer?
Yes. The randomized phase III CHAARTED and STAMPEDE clinical trials demonstrated a significant improvement in OS with the addition of 6 Tx of
docetaxel chemo to standard ADT. In the CHAARTED study, this clinical benefit was most pronounced in pts presenting with a “high-burden” of metastatic Dz, as defined by the presence of visceral mets and/or highvolume osseous mets. (Sweeney CJ et al., NEJM 2015; James ND et al., Lancet 2016)
Typically, how long after initiating ADT does it take before a pt’s prostate cancer becomes castration-resistant?
Castration-resistance usually occurs within 18–24 mos of starting ADT. (Eisenberger MA et al., NEJM 1998, Sweeney CJ et al., NEJM 2015)
What are the commonly used initial management strategies for pts with new progression to castration-resistant prostate cancer?
If CAB is being administered, withdrawal of the AA may result in a temporary PSA decline. If a GnRH analog alone is being given, the addition of an AA may help.
