NEW FRONTIERS IN PROSTATE CANCER MANAGEMENT
From Perspectives in Urology: Point Counterpoint, presented by Grant/Downing Education
Educational Objectives
| The goal of this program is to improve the chemotherapeutic management of prostate cancer. After hearing and assimilating
this program, the clinician will be better able to:
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 | 1. State the advantages and disadvantages of docetaxel as chemotherapy for prostate cancer.
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| 2. Discuss ways of managing skeletal complications of prostate cancer chemotherapy.
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| 3. Describe the general strategy underlying many new chemotherapeutic agents for prostate cancer.
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| 4. Explain why vascular endothelial growth factor (VEGF) is the target of so many new drugs.
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| 5. Compare the advantages and disadvantages of injections and implants for hormone therapy of prostate cancer.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the
planning committee to disclose relevant financial relationships within the past 12 months that might create any personal
conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes
quality in health care and not a proprietary business or commercial interest. For this program, the following has been
disclosed: Dr. Quinn receives grant support form Sanofi-Aventis, Genentech, and Millenium, and is on the Speakers’
Bureau for Sanofi-Aventis, Millenium, Chiron, Onyx, Bayer, MGI Pharm, Merck, OSI, and Abbott, and serves on the
advisory board of Abbott, Threshold, and OSI. Dr. Crawford receives grant support from the National Institutes of
Health, Oncura, and the University of Colorado Cancer Center, and is on the Speakers’ Bureaus of Auxilium Pharmaceuticals,
GlaxoSmithKline, and Sanofi-Aventis. Dr. Morgentaler receives grant support from Auxilium Pharmaceuticals,
AMS, Indevus Pharmaceuticals, Mentor, and Solvay, and is on the Speakers’ Bureaus of Auxilium
Pharmaceuticals, AMS, Indevus Pharmaceuticals, Lilly, Mentor, and Solvay.
Acknowledgements
This program was recorded at Perspectives in Urology: Point Counterpoint, held November 8-10, 2007, in Scottsdale,
AZ, and sponsored by Grant/Downing Education. The Audio-Digest Foundation thanks the speakers and the
sponsor for their cooperation in the production of this program.
| CHEMOTHERAPY FOR ADVANCED PROSTATE CANCER 2008—David Quinn, MD, PhD, Assistant Professor
of Clinical Oncology, Department of Medicine, the Keck School of Medicine at the University of Southern California;
Director and Co-Leader, Genitourinary Cancer Program, and Head, Genitourinary Section, Division of Cancer
Medicine and Blood Diseases, University of Southern California/Norris Cancer Center, Los Angeles
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| Standard of care: does not exist for chemotherapy after prostatectomy or with radiation therapy, even for locally
advanced disease
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| Barriers to providing chemotherapy to patients with advanced prostate cancer: on average, patients become
hormone-refractory 2 yr after starting hormone therapy; next step usually requires consultation with physician
other than urologist; medical oncologists may downplay side effects of drugs, or believe drugs more effective than
they really are
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| Clinical trials: by 1993, 54 trials of cytotoxic agents conducted in United States on patients with advanced prostate
cancer; outcome “absolutely nothing”; first successful trial of chemotherapy for hormone-refractory prostate
cancer conducted in Canada with mitoxantrone plus prednisone; found advantage of ≈2 mo in median time to
progression; no survival advantage observed; however, pain palliated for average of 6 mo; currently used as second-
or third-line therapy; study 9916 from Southwest Oncology Group (SWOG 9916)—compared docetaxel
plus estramustine to mitoxantrone plus prednisone; >600 patients enrolled; survival advantage with docetaxel
regimen ≈2 mo; statistically significant “but kind of disappointing;” availability of docetaxel combination to patients
who failed mitoxantrone regimen may have reduced survival advantage between groups; after 1 yr on either
treatment, 80% of patients require further treatment for progression-free survival; prostate-specific antigen
(PSA)—value as surrogate for outcome debated; reduction does not account for 100% of chemotherapy effect
observed; among patients with 50% decline in PSA levels, mean survival 21 mo, compared to survival of 14 to
15 mo associated with smaller PSA reduction; patients who respond may do so to either therapy, but response to
docetaxel regimen more likely; in follow-up study, docetaxel administered every 3 wk without estramustine
showed >2 mo survival advantage over mitoxantrone; advantage not seen when docetaxel administered weekly;
docetaxel now first-line treatment of choice, although best candidates not yet completely defined; confers survival
advantage to symptomatic and asymptomatic patients who fulfill hormone-refractory criteria
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| Satraplatin and Prednisone Against Refractory Cancer (SPARC) trial: enrolled patients who had failed first-line
treatment; subjects received oral satraplatin, prednisone, and antiemetics 5 days/wk for 7 wk; control group received
placebo; patients continued treatment until disease progressed or they could no longer tolerate therapy; no
clinical significance in median progression-free survival (8 days); however, satraplatin associated with better stabilization
beyond median time point; satraplatin much better tolerated than other platin drugs (does not cause
neuropathy or renal impairment); does affect blood count; all in all, good option for frail elderly patients; investigators
concluded that satraplatin of value because it is better tolerated, although it does not significantly increase
survival; can be taken orally, making it easy for patients
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| Skeletal complications: Androgen-Independent Prostate Cancer Study of Calcitriol Enhancing Taxotere
(ASCENT)—megadoses of vitamin D given before docetaxel on weekly basis; results compared to docetaxel
plus placebo; 125 patients in each arm; vitamin D associated with fewer serious adverse events related to docetaxel;
ASCENT-2 enrolled 900 of 1200 patients before being terminated due to excess of adverse events among
vitamin D group; results now being analyzed
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| Zoledronic acid: good for prophylaxis; decreases incidence of skeletal events, prolongs time to first skeletal event;
administered intravenously every 4 wk; also associated with trend toward longer survival; patients given
zoledronic acid require fewer morphine equivalents to control pain; however, bisphosphonates associated with
risk for jaw necrosis (more likely in patients with myeloma than prostate cancer)
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| NOVEL NEW AGENTS —Dr. Quinn
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| Overview: targets of new agents are receptors and ligands in milieu where cancer flourishes, eg, bone, vascular endothelium;
elevation of markers of increased bone resorption (N-telopeptide) and production (bone-specific alkaline
phosphatase) predict early mortality
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| Metastasis of prostate cancer: involves cancer cell, osteoblast, osteoclast; cancer cell—proliferates in bone
marrow; osteoblast—involved in production of sclerotic metastases; osteoclasts—involved in bone degradation;
these 3 cell types communicate with each other
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| Endothelin-1: serum levels normal when patient healthy or disease localized (before prostatectomy); median levels
double in patients with hormone-refractory disease; occupies endothelin-A receptors
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| Drugs that target endothelin-1 activity: ZD4054—blocks endothelin-A receptors; in clinical trials, reduced risk
for death by nearly 50% and prolonged overall median survival by 6 to 7 mo (both findings statistically significant);
atrasentan—acts directly on endothelin-1; compared to placebo, significantly delays development of
bone metastases; however, not all patients respond, and drug does not kill cancer cells; drug slows PSA increase
but does not reduce it; in some patients, atrasentan does produce slight initial reduction in bone alkaline
phosphatase levels
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| Ongoing SWOG study: patients required to have bone metastases (believed that only these patients benefit from
atrasentan); 3 components—docetaxel (most effective killer of prostate cancer cells in castrate hormone-refractory
environment); atrasentan (to inhibit osteoblast activity); bisphosphonates (most effective inhibitors of osteoclast
activity)
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| Angiogenesis: vascular endothelial growth factor (VEGF) pathway consists of series of ligands, including placental
growth factor and VEGF A to D; ≥3 receptors involved; several pathways, but mitogenic effects on vasculature
with endothelial migration most thoroughly studied; this part of pathway may also prove most promising for preventing
metastases, which often involve lymphatic vessels; bevacizumab (Avastin) targets VEGF (trial ongoing);
other agents being studied that target pericytes (sit behind endothelial cells); suitability of VEGF as drug target—
elevations of VEGF portend worse prognosis; bevacizumab alone does not seem to have much effect, but in trial of
patients with colorectal cancer, adding it to standard chemotherapy regimen associated with 6-mo extension of survival;
in Docetaxel and Prednisone With Versus Without Bevacizumab in Patients with Hormone-Refractory Metastatic
Adenoma of the Prostate trial (CALGB-90401), bevacizumab associated with high complete and partial
response rates; BAY 43-9006 (Sorafenib)—acts through VEGF receptor; one small study halted early due to rise in
PSA levels associated with drug; however, further analysis showed reversal of bone metastases; BAY 43-9006 may
be differentiating agent that produces slight elevation in PSA levels, which then plateau; mammalian target of rapamycin
(mTOR)—abnormal levels associated with advanced cancer of kidney, bladder, lung, and prostate; several
mTOR inhibitors now being studied
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| CB 7630 (abiraterone): targets nontesticular androgenic steroid synthesis; associated with promising effects on
PSA levels in clinical trials; oral agent; blocks adrenal steroid metabolism; affects aldosterone as well as androgenic
steroids, leading to side effects such as hypertension, hypokalemia, and fluid overload; may be more effective
than ketoconazole at treating advanced prostate cancer
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| Immunotherapy: 2 vaccines (sipuleucel-T [Provenge]; GVAX) showing encouraging results; sipuleucel-T targeted
toward single antigen, may not be beneficial if patient does not have that antigen; GVAX polyvalent vaccine,
but may not affect appropriate antigens, and may produce more adverse effects than sipuleucel-T; with
sipuleucel-T, patients undergo leukapheresis to obtain dendritic cells (antigen-presenting cells [APCs]), which
are cultured with prostatic acid phosphatase (PAP), then reinfused; one course of therapy projected to cost
$65,000-$100,000; treatment goal to activate APCs against PAP, attack cancer cells, and mediate immune response
by activating T cells and other immune cells; GVAX combines 2 prostate cancer cell lines modified with
granulocyte-macrophage colony stimulating factor (GM-CSF); injected subcutaneously; objective to mimic antigen
expression of hormone-refractory prostate cancer cells
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| Clinical findings: sipuleucel-T—just missed statistical significance on primary end point (progression-free survival);
overall survival significantly higher, but study involved only 127 patients; FDA requested larger studies
(now under way); GVAX—phase 2 studies showed partial response and significant stability in PSA levels; in
some patients with skeletal metastases, bone scans returned to normal; side effects erythema, pruritus, induration
of skin at injection site, as well as flu-like symptoms; outcome exceeded predictions developed from CALGB
data (phase 3 ongoing)
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| LHRH THERAPY: INJECTIONS VS. IMPLANTS
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| LHRH INJECTIONS —Abraham Morgentaler, MD, Associate Clinical Professor of Urology, Harvard Medical
School, Boston, MA, and Director, Men’s Health Boston
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| History: started as monthly treatments in 1980s; several competing products available; all luteinizing hormone-releasing
hormone (LHRH) agonists that initially promote but ultimately suppress testosterone synthesis through
negative feedback loop; 12-mo implants available for past several years; disadvantages of treatment with LHRH
agonists—negative effects (hot flushes, low libido) persist long after cessation of treatment; some patients never
recover normal testosterone levels; effect may correspond to duration of therapy or cumulative dosage (take both
into account if treatment cessation planned); advantages—flexible treatment schedule; patient must come to office,
so treatments can be combined with physical examination or measurement of PSA levels; patient has reassurance
that doctor spending time with him; treatment can be shortened or discontinued whenever necessary;
disadvantages of implants—premature extrusion or other unpredictable effects; implantation requires surgical procedure
by physician (nurse can administer injections); palpable, sometimes visible; patients may feel slighted if
seen only at 6- or 12-mo intervals
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| LHRH IMPLANTS —E. David Crawford, MD, Professor of Surgery, Urology, and Radiation Oncology, Head, Section
of Urologic Surgery, and E. David and Vicki M Crawford Endowed Chair in Urologic Oncology, University of
Colorado Health Sciences Center, Denver
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| Duration of implants: several 12-mo products available; 6-mo implants recently approved
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| Side effects of hormone therapy: decrease in testosterone to castrate levels may lead to hot flushes; injections
sometimes associated with injection-site reactions, eg, pain; erectile dysfunction; fatigue; diminished libido; implants
can be removed if necessary
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| Disadvantages of injections: patients dislike injections; injections hurt; hassle factor (inconvenience of repeated
visits to physician’s office; time spent by medical staff preparing and administering injections); drugs remain in
system for 3 to 4 mo; effects not controllable
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| Advantages of implants: can be administered subcutaneously, in office, without need for surgery; good data suggest
testosterone remains at castrate levels throughout year; removable if necessary; less loss to follow-up, thanks
to greater patient convenience; easier inventory control, supply management, billing, and lower associated costs;
lower risk for errors; higher Current Procedural Terminology (CPT) codes for implantation and removal than injections;
frees doctor to spend more quality time with patients; beneficiaries include patients who live far from office,
travel frequently, have busy work schedules, or cannot drive themselves
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Suggested Reading
Corey E et al: Zoledronic acid exhibits inhibitory effects on osteoblastic and osteolytic metastases of prostate cancer.
Clin Cancer Res 9:295, 2003; Grant JP Jr, Levinson AW: Anaphylaxis to leuprolide acetate depot injection
during treatment for prostate cancer. Clin Genitourin Cancer 5:284, 2007; Lara PN Jr, Twardowski P, Quinn
DI: Angiogenesis-targeted therapies in prostate cancer. Clin Prostate Cancer 3:165, 2004; Lebret T, Bouregba
A: Roles of the urologist and nurse from the perspective of patients with prostate cancer receiving luteinizing hormone-releasing
hormone analogue therapy. BJU Int June 11, 2008 [Epub ahead of print]; Marx RE et al: Bisphosphonate-induced
exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and
treatment. J Oral Maxillofac Surg 63:1567, 2005; O’Donnell A et al: Hormonal impact of the 17alpha-hydroxylase/C(17,20)-lyase
inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. Br J Cancer 90:2317,
2004; Schlegel PN, Histrelin Study Group: Efficacy and safety of histrelin subdermal implant in patients with advanced
prostate cancer. J Urol 175:1353, 2006; Shiota M et al: Injection-site granulomas resulting from the administration
of both leuprorelin acetate and goserelin acetate for the treatment of prostate cancer. J Nippon Med Sch
74:306, 2007; Small EJ et al: Granulocyte macrophage colony-stimulating factor—secreting allogeneic cellular
immunotherapy for hormone-refractory prostate cancer. Clin Cancer Res 13:3883, 2007; Tu SM, Lin SH: Current
trials using bone-targeting agents in prostate cancer. Cancer J 14:35, 2008; Warren R, Liu G: ZD4054: A specific
endothelin A receptor antagonist with promising activity in metastatic castration-resistant prostate cancer. Expert
Opin Investig Drugs 17:1237, 2008.
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