Radiation Oncology: A Question-Based Review

Metastatic Prostate Cancer

Richard Tuli and Naomi B. Haas

image 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 2004Katz MS et al., J Clin Oncol 2004Stephenson RA et al., JAMA 2004; Zhou P et al., J Clin Oncol 2005)

What are the common sites of mets for prostate cancer?

The most common sites are the bones of the axial skeleton. These lesions are usually osteoblastic but can be lytic as well.

image 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?

Both 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 1998Kane CJ et al., Urology 2003)

Are other imaging modalities useful or being investigated to aid in Dx?

Yes. Other imaging modalities under investigation include MRI of the axial skeleton, MRI with endorectal coil, and ProstaScint.

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., J Clin Oncol 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.

Is ProstaScint useful in diagnosing localized and/or metastatic prostate cancer?

The data are mixed regarding the utility of ProstaScint. Most studies have shown it to have a poor PPV for detecting extraprostatic Dz (Nagda SN et al., Int J Radiat Oncol Biol Phys 2007Thomas CT et al., J Clin Oncol 2003). B/c its interpretation is confounded by reader experience and the timing of imaging, it is not commonly included as part of the workup for localized or metastatic recurrence.

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., J Clin Oncol 1999)

image Treatment/Prognosis

What is 1st-line systemic therapy for metastatic prostate cancer?

AS by orchiectomy or, more commonly, the use of a GnRH analog 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 et al. revealed that androgen deprivation through castration and 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 antagonists), estrogens, and ketoconazole (antifungal agent, blocks cyt P450 enzymes involved in steroidogenesis)

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 (ELAAT, 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 as compared to 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 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 suggesting at least similar outcomes. (Hussain M et al., J Clin Oncol 2006; Salonen AJ et al., J Urol 2008; Shaw GL et al., BJU Int 2007)

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. Consider palliative focal or systemic radiotherapy as appropriate in conjunction with a bisphosphonate (refer to Chapter 88).

What is the role of ketoconazole in the Tx of metastatic prostate cancer?

Ketoconazole, a commonly used antifungal, inhibits steroidogenesis and is cytotoxic to prostate cancer cells. It is commonly prescribed for castration-resistant prostate cancer with hydrocortisone to prevent adrenal insufficiency and often results in GI and liver toxicity. Its use is associated with a 20%–50% reduction in PSA with a 3–6 mo duration of response. (Ryan CJ et al., Curr Oncol Rep 2005)

What are chemo-therapeutic options for pts with metastatic hormone-refractory prostate cancer?

Docetaxel/prednisone is now the standard of care for metastatic, hormone-refractory prostate cancers based on 2 key randomized trials, TAX 327 and SWOG 9916.

The TAX-327 trial (Tannock IF et al., NEJM 2004) randomized 1,006 men to 3 Tx arms: 2 doses of docetaxel (30 mg weekly or 75 mg q3wks) and mitoxantrone in progressive metastastic, hormone-refractory prostate cancer pts who were chemo naive. All 3 groups rcv prednisone and were continued on AS. The mitoxantrone arm had significantly worse OS compared to the q3wk docetaxel arm, but was not significantly worse than the qwk docetaxel arm (MS was 18.9 mos vs. 17.4 mos vs. 16.5 mos, in q3wks, qwk docetaxel, and mitoxantrone arms, respectively). There was greater improvement in PSA, pain, and QOL with docetaxel but increased grade 3–4 toxicity (neutropenia, n/v, diarrhea).

The SWOG 9916 trial (Petrylak DP et al., NEJM 2004) randomized 770 men to estramustine/docetaxel/dexamethasone vs. mitoxantrone/prednisone. The docetaxel arm had significantly improved MS (17.5 mos vs. 15.6 mos) and PSA response (50% vs. 27%). There were more grade 3–4 toxicities (neutropenic fever, n/v, cardiovascular events) in the docetaxel arm.

What is the potential advantage of degarelix in the Tx of prostate cancer?

Degarelix, a newly FDA-approved GnRH antagonist, can produce a faster reduction of testosterone levels and avoid the initial flare. Common side effects, however, include local and systemic inflammatory reactions.

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 is pending.

2.     Gene transfer cytoreduction is designed to express lytic viruses (e.g., CV706/E1a) that preferentially target prostate cancer cells.

3.     Endothelin receptor antagonists (e.g., ZD4054, atrasentan) are designed to prevent inhibition of apoptosis in prostate cancer cells. RCTs have not shown benefit of atrasentan compared to placebo. SWOG 0421 is under way.

4.     Monoclonal antibody therapies (e.g., cetuximab, trastuzumab) are being explored in phase I–II studies.

5.     17α-hydroxylase/17,20 lyase inhibitors (e.g., abiraterone) are in phase III trials in both chemo-naive castrated pts and in those with prior docetaxel therapy.

6.     Selective androgen receptor modulators (e.g., MDV3100) are undergoing phase III evaluation in castrated pts who have failed 1–2 prior chemo regimens.

7.     Mature data is awaited on 1st-line docetaxel and prednisone +/− bevacizumab in castrated pts with metastatic Dz.

image Toxicity

What are the common short-term and long-term side effects of AS?

1.     Short-term effects: hot flashes, ↓ libido, fatigue

2.     Long-term effects: gynecomastia, anemia, ↓ muscle mass, ↓ bone density, obesity, mood changes, dyslipidemia, insulin resistance, possibly diabetes and coronary artery Dz

(Higano CS, Urology 2003Keating NL et al., J Clin Oncol 2006)

What are common side effects associated with AA therapy, and how long is the Tx course?

Common side effects of bicalutamide, which is most commonly prescribed 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.