Advances in Prostate Cancer Chemotherapy
`
`Advances in Prostate Cancer
`Chemotherapy: A New Era Begins1
`
`Kenneth J. Pienta, MD2; David C. Smith, MD
`
`Dr. Pienta is Professor of Medicine
`and Urology, American Cancer So-
`ciety Clinical Research Professor,
`Michigan Urology Center, University
`of Michigan, Ann Arbor, MI.
`
`Dr. Smith is Director, Multidisci-
`plinary Urologic Oncology Clinic,
`Associate Professor of Medicine and
`Urology, University of Michigan
`Comprehensive Cancer Center, Ann
`Arbor, MI.
`
`This article is available online at
`http://CAonline.AmCancerSoc.org
`
`ABSTRACT Prostate cancer continues to be the most common lethal malignancy diagnosed
`in American men and the second leading cause of male cancer mortality. Over 60 years ago,
`Huggins and Hodges discovered androgen deprivation as a first-line therapy for metastatic
`prostate cancer, which leads to remissions typically lasting 2 to 3 years, but in most men
`prostate cancer ultimately progresses to an androgen-independent state resulting in death due
`to widespread metastases. Multiple mechanisms of androgen independence have now been
`documented, including amplification of the androgen receptor as well as signal transduction
`pathways that bypass the androgen receptor completely. In 2004, two landmark studies dem-
`onstrated a survival advantage in androgen-independent prostate cancer patients utilizing
`docetaxel chemotherapy, setting a new standard of care for this disease. In addition, treatments
`with the bisphosphonate zoledronic acid and systemic radioisotopes have also been shown to
`have palliative benefits in this population. Building on these advances, several new traditional chemotherapeutic agents as well as new
`targeted therapies are under development. (CA Cancer J Clin 2005;55:300–318.) © American Cancer Society, Inc., 2005.
`
`INTRODUCTION
`
`Prostate cancer continues to be the most common lethal malignancy diagnosed in American men and the second
`leading cause of male cancer mortality. The American Cancer Society estimates that during 2005 about 232,090 new
`cases of prostate cancer will be diagnosed in the United States and 30,350 men will die of metastatic disease.1 About
`1 man in 5 will be diagnosed with prostate cancer during his lifetime, and 1 man in 33 will die of this disease. As
`the population ages, these numbers are expected to increase. Over 60 years ago, Huggins and Hodges discovered
`androgen deprivation as a first-line therapy for metastatic prostate cancer.2,3 Hormonal therapy leads to remissions
`typically lasting 2 to 3 years, but in most men metastatic prostate cancer ultimately progresses to an androgen-
`independent state resulting in death due to widespread metastases.4-8 Bone metastases are accompanied by an
`osteoblastic reaction in the bone that is unmatched by any other type of cancer (Figure 1). Autopsy studies reveal that
`metastases to other organs are prevalent with common sites including lymph nodes, lung, adrenal glands, and liver.
`
`MECHANISMS OF ANDROGEN RESISTANCE
`
`During androgen-dependent progression, prostate cancer cells depend primarily on the androgen receptor for growth
`and survival.9-11 When testosterone enters the cell, it is converted to its active metabolite dihydrotestosterone (DHT) by
`the enzyme 5␣reductase. DHT then binds androgen receptors in the cytoplasm and translocates into the nucleus, binding
`to the androgen-response elements within the DNA and thereby activating genes involved in cell growth.9 During
`androgen-independent progression, prostate cancer cells develop a variety of cellular pathways to survive and flourish in
`the androgen depleted environment (Figure 2).9-14 The first pathway has been referred to as the hypersensitive pathway. In
`this pathway, more androgen receptor (AR) is produced by the cell and may be activated despite reduced levels of
`
`1This work was supported by 2 P50 CA6,9568 – 06A1, NIH 1 R01 CA1,02872, NIH 1 PO1 CA0,93900 – 01A2, and The Prostate Cancer Foundation.
`2Dr. Pienta is supported by the ACS as a Clinical Research Professor.
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`FIGURE 1 Osteoblastic Metastases in Bone. The osteoblastic reaction common to prostate cancer is demonstrated in
`the hip of a patient with late-stage prostate cancer.
`
`dihydrotestosterone. This increased production of
`AR is likely the result of the prostate cancer cells
`developing more copies of the AR gene (gene
`amplification) as a result of mutation or through
`selective pressure of the androgen-depleted envi-
`ronment, causing the cells with fewer androgen
`receptors to die off and the clonal expansion of
`cells with more AR. It is likely that hormone
`refractory prostate cancer is not “androgen inde-
`pendent” in the classic sense, but rather “castration
`independent” and that the cancer is now able to
`use very low levels of androgen to grow.
`The specificity of the AR can also be broad-
`ened by mutations, creating a promiscuous receptor
`that can be activated by nonandrogenic steroid
`molecules normally present in the circulation.9-11
`To be activated, the AR must be phosphorylated
`and this phosphorylation can be accomplished by
`other nonsteroid molecules through two separate
`pathways. In one pathway, termed the outlaw
`
`pathway, molecules such as deregulated growth
`factors and cytokines directly phosphorylate and
`activate the AR. In the second pathway, termed
`the bypass pathway, cell survival occurs indepen-
`dent of AR activation. The best example of this
`pathway is the upregulation of the molecule
`BCL-2 by androgen-independent prostate cancer
`cells which protect them from apoptosis or pro-
`grammed cell death when they are exposed to
`lack of testosterone.
`Other postulated mechanisms of androgen in-
`dependence include the involvement of cells that
`support the growth of the cancer cells. For ex-
`ample, neuroendocrine cells may secrete neu-
`ropeptides that induce the growth of androgen-
`independent cancer cells. Alternatively, prostate
`cancer stem cells may be present in the prostate
`tumor,
`supporting the growth of androgen-
`independent cells as the androgen dependent cells
`regress as a result of hormone therapy.
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`FIGURE 2 Possible Pathways to Androgen Independence. (1) In the outlaw pathway, receptor tyrosine kinases (RTKs) are activated, and the
`androgen receptor (AR) is phosphorylated by either the AKT (protein kinase B) or the mitogen-activated protein kinase (MAPK) pathway, produc-
`ing a ligand-independent AR. (2) In the promiscuous pathway, the specificity of the AR is broadened so that it can be activated by nonandrogenic
`steroid molecules normally present in the circulation. (3) In the hypersensitive pathway, more AR is produced (usually by gene amplification), AR
`has enhanced sensitivity to compensate for low levels of androgen, or more testosterone is converted to the more potent androgen, dihydrotestos-
`terone (DHT), by 5␣ reductase. (4) In the bypass pathway, parallel survival pathways, such as that involving the antiapoptotic protein BCL-2 (B-
`cell lymphoma 2), obviate the need for AR or its ligand. (5) In the stem-cell repopulation pathway, androgen-independent cancer stem cells are
`resistant to therapy and eventually grow out and eventually become the primary population within the tumor.
`
`THE EVOLUTION OF CHEMOTHERAPY FOR HORMONE
`REFRACTORY PROSTATE CANCER: THE PRETEXANE ERA
`
`In 1993, Yagoda and Petrylak wrote a defini-
`tive review on the use of chemotherapy in pa-
`tients with hormone refractory prostate cancer.15
`Earlier reviews had reported objective responses
`
`in the form of complete and partial remissions in
`approximately 6.5% of patients treated with an-
`thracyclines, alkylating agents, antimetabolites,
`platinums, and topoisomerase inhibitors. In their
`review of 26 new trials published in the years
`1987 to 1991, they found an overall response rate
`of 8.7% (95% confidence interval, 6.4% to 9.0%)
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`CA Cancer J Clin 2005;55:300–318
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`and concluded that hormone-refractory prostate
`cancer was unresponsive to cytotoxic agents.15
`They further noted that documentation of re-
`sponse was complicated by a lack of established
`criteria to judge activity in a disease in which few
`patients had measurable soft tissue lesions. They
`noted that: “Chaos will continue to reign when
`the efficacy of one drug is reported to be 0 to
`85%...when investigators continue to include sta-
`ble disease findings within a so-called objective
`response category, thereby intimating that signif-
`icant prostate cancer cell death has occurred.”15
`In 1997, Raghavan and colleagues reinforced the
`concept that the clinical utility of cytotoxic ther-
`apy in advanced prostate cancer was undefined
`and that this was partially attributable to the lack
`of established criteria for judging response in
`treatment of a disease that was largely evident by
`bone scan only.16
`Before the prostate-specific antigen (PSA) era,
`classic response rates could only be determined in
`the minority of patients with measurable disease
`(approximately 10% to 20%). Controversy ex-
`isted as to whether these patients with soft tissue
`disease were representative of advanced prostate
`cancer patients in general who only had metasta-
`ses to bone. In the early 1990s, PSA assays became
`widely available and response to agents in clinical
`trials began to be measured and reported in terms
`of PSA response.17-21 In Phase II trials, a decline
`in PSA by 50% appeared to correlate with in-
`creased survival.17 In 1999, a consensus confer-
`ence suggested that a partial response in clinical
`trials be defined as a minimum a PSA decline of at
`least 50% confirmed by a second PSA value 4 or
`more weeks later in the absence of clinical or
`radiographic evidence of disease progression dur-
`ing this time period.19 The use of the PSA end-
`point, although not validated in a Phase III trial as
`a surrogate for response or survival, has become
`the standard method to screen for activity in
`Phase II trials.
`
`CHEMOTHERAPY FOR HORMONE REFRACTORY
`PROSTATE CANCER: THE TAXANES
`
`cluding vinblastine, paclitaxel, and docetaxel.22-27
`Several Phase II studies were initiated based on the
`preclinical data. The most active agent preclinically
`and clinically was docetaxel, either alone or in
`combination with estramustine.28-30 Docetaxel, a
`semisynthetic taxane, likely has multiple mecha-
`nisms of antineoplastic activity. Microtubule stabi-
`lization, the most widely accepted mechanism of
`action, involves binding of docetaxel to ␤-tubulin,
`thus promoting polymerization (Figure 3). In nor-
`mal cellular division, microtubules act as the cy-
`toskeleton for the mitotic spindle. Under usual
`conditions, microtubules undergo polymerization
`in the presence of microtubule-associated proteins.
`Once bound by taxanes, microtubules cannot be
`disassembled. This static polymerization disrupts
`the normal mitotic process, usually arresting cells in
`the G2M phase of the cell cycle, ultimately leading
`to apoptosis. Estramustine is known to bind to
`microtubule associated proteins and one proposed
`mechanism for this agent is to act in concert with
`the taxanes to inhibit microtubule function.
`A second proposed mechanism for the cy-
`totoxicity of docetaxel is that it can counter the
`prosurvival effects of BCL-2 expression. It has
`been demonstrated that BCL-2 overexpression
`protects prostate cancer cells from apoptosis
`after androgen withdrawal, and that increased
`BCL-2 expression confers both chemo- and
`androgen-resistance.31-33 The BCL-2 gene is
`part of a class of oncogenes that contributes to
`neoplastic progression by inhibition of apopto-
`tic cell death. Phosphorylation of BCL-2 pro-
`tein leads
`to loss of BCL-2 antiapoptotic
`function.34 Docetaxel
`induced microtubule
`stabilization arrests cells in the G2M phase,
`inducing BCL-2 phosphorylation and forcing
`the continued activation of the caspase cascade,
`leading to increased apoptosis. Other studies
`have reported multiple other proapoptotic ef-
`fects of docetaxel, including effects on BCL-
`xL,
`induction of p53, ability to overcome
`multidrug resistance and antiangiogenic prop-
`erties.28
`
`Starting in the 1990s, preclinical studies demon-
`strated that prostate cancer cells appeared to be
`especially sensitive to mitotic spindle inhibitors in-
`
`PHASE I/II CLINICAL STUDIES OF DOCETAXEL
`
`Several Phase II trials evaluated docetaxel as
`a single agent in patients with hormone refrac-
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`FIGURE 3 Docetaxel Has Multiple Mechanisms of Antineoplastic Activity. Microtubule stabilization involves binding of docetaxel to ␤-tubulin,
`thus promoting polymerization. In normal cellular division, microtubules act as the cytoskeleton for the mitotic spindle. Under usual conditions, mi-
`crotubules undergo polymerization in the presence of microtubule-associated proteins. Once bound by taxanes, microtubules cannot be disassem-
`bled, disrupting the cell and leading to programmed cell death (apoptosis).
`
`tory prostate cancer. The pharmacokinetics of
`docetaxel are linear with dose and remain in-
`dependent of schedule. A variety of weekly and
`every 3-week schedules have been evaluated.35
`Results of these studies are summarized in Ta-
`ble 1. Response rates by PSA criteria ranged
`from 38% to 48%. Neutropenia was the prin-
`cipal toxicity, occurring in up to 70% of pa-
`tients treated on an every 3-week schedule.
`Neutropenia was less common on the weekly
`schedule with similar response rates. Clearance
`of docetaxel is primarily via hepatic metabolism
`with increased toxicity associated with de-
`creased hepatic metabolism. Other notable
`toxicities include fluid retention, rash, and pe-
`ripheral neuropathy. Premedication with ste-
`roids
`is used to decrease the risk of
`fluid
`retention. Response rates as high as 70% were
`seen in the studies that investigated the com-
`bination of estramustine and docetaxel. Side
`effects were significant, with neutropenia in up
`
`to 70% of patients and thrombosis in up to
`10%. Fatigue and hyperglycemia were also
`common. Based on these studies, Phase III
`trials of docetaxel and the combination of do-
`cetaxel and estramustine were designed.
`
`PHASE III STUDIES OF DOCETAXEL IN HORMONE
`REFRACTORY PROSTATE CANCER
`
`Two Phase III trials of docetaxel in men
`with hormone refractory disease were reported
`in 2004. Both demonstrated a survival advan-
`tage and docetaxel has become the new stan-
`dard of care for first-line treatment in this
`setting. Both trials randomized docetaxel verses
`mitoxantrone, an agent that has been shown to
`improve quality of life but failed to demon-
`strate a survival benefit.44
`The Southwest Oncology Group (SWOG)
`9916 trial, docetaxel and estramustine compared
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`Table 1 Examples of Trials of Single-agent Docetaxel and Combined Chemotherapy Regimens for Androgen-independent
`Prostate Cancer
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`CA Cancer J Clin 2005;55:300–318
`
`Trial
`
`Docetaxel
`
`Combination
`
`Picus and Schultz36 (1999)
`Friedland, et al.37 (1999)
`Berry, et al.38 (2001)
`
`75 mg/m2 every 21 days
`75 mg/m2 every 21 days
`36 mg/m2 weekly for 6 of 8 weeks
`
`Not available
`Not available
`Not available
`
`Beer, et al.39 (2001)
`Gravis, et al.40 (2003)
`Petrylak, et al.41 (2000)
`
`36 mg/m2 weekly for 6 of 8 weeks
`35 mg/m2 weekly for 6 of 8 weeks
`70 mg/m2 every 21 days
`
`Sinibaldi, et al.42 (2002)
`
`70 mg/m2 every 21 days
`
`Savarese, et al.43 (2001),
`CALGB 9780
`
`70 mg/m2 every 21 days
`
`Not available
`Not available
`Estramustine 280 mg three times a
`day for days 1–5
`Estramustine 280 mg every 6
`hours ⫻ 5 doses; coumadin 2 mg
`daily
`Estramustine 10 mg/kg/day in three
`daily doses for days 1–5;
`hydrocortisone 30 mg every morning
`and 10 mg every afternoon daily
`Estramustine 280 mg three times a
`day for days 1–5
`Prednisone 5 mg twice daily
`
`60 mg/m2 every 21 days
`
`75 mg/m2 every 21 days
`
`Petrylak, et al.44 (2004), SWOG*/
`Intergroup (Phase III)
`Tannock, et al.45 (2004), TAX-327
`(Phase III)
`
`*Southwest Oncology Group
`
`30 mg/m2 weekly for 5 of 6 weeks
`
`Prednisone 5 mg twice daily
`
`Patients
`with > 50%
`Decline in
`Prostate-
`Specific
`Antigen
`Level (%)
`
`46
`38
`41
`
`46
`48
`68
`
`45
`
`68
`
`50
`
`45
`
`48
`
`Patients with
`a Soft Tissue
`Response
`(%)
`
`24
`29
`33 (complete
`response: 17)
`40
`28 (stable disease)
`55
`
`Overall
`Survival
`
`27 months
`67% at 15 months
`9.4 months
`
`39 weeks
`20 months
`77% at 1 year
`
`20
`
`13.5 months
`
`50 (partial
`response: 38;
`complete
`response: 13)
`17
`
`12
`
`8
`
`20 months
`
`18 months
`
`18.9 months
`
`17.3 months
`
`with mitoxantrone and prednisone for advanced
`refractory prostate cancer, accrued 770 patients,
`randomizing them to mitoxantrone (12 mg/m2)
`and prednisone (5 mg twice daily) versus do-
`cetaxel 60 mg/m2 on Day 2 and estramustine 280
`mg/m2 3 times daily on Days 1 to 5, each on a
`21-day cycle.44 The primary endpoint was over-
`all survival and secondary endpoints included
`progression-free survival, objective response rate,
`and rate of PSA decline. Patient stratification was
`to type of progression (PSA only or evaluable
`disease), pain, and performance status. Overall
`survival was significantly higher in the docetaxel/
`estramustine (D/E) arm when compared with the
`mitoxantrone/prednisone
`(M/P)
`arm (17.5
`months versus 15.6 months, P ⫽ 0.01). Also
`statistically significant were PSA response rate
`(50% for D/E versus 27% for M/P) and objective
`response rate in patients with measurable soft
`tissue disease (17% versus 11%, respectively).
`Neutropenia (Grades 3 to 5) was similar for both
`groups (D/E: 16.1%, M/P: 12.5%) but the D/E
`group did have higher rates of neutropenic fever,
`
`cardiovascular events, nausea and vomiting, met-
`abolic disturbances, and neurologic events. In all,
`66 patients treated with D/E had Grade 3 or
`above nausea and vomiting (20%) compared with
`17 in the M/P group (5.1%) (P ⬍ 0.001). There
`were 2 episodes of Grade 3 thrombosis and 11
`episodes of Grade 4 thrombosis noted in the D/E
`group and none in the M/P group, but this
`difference was not statistically significant. There
`were 48 cardiovascular events of Grade 3 or
`greater in the D/E group (14.5%) and 22 in the
`M/P group (6.7%) (P ⫽ 0.001). The authors’
`conclusion was
`that docetaxel/estramustine
`should be considered a standard of care for men
`with advanced prostate cancer secondary to a
`20% increase in overall survival, an increase in
`progression-free survival, and higher PSA and
`objective response rates (Figure 4A).36
`The second multicenter trial, TAX 327, do-
`cetaxel plus prednisone or mitoxantrone plus
`prednisone for advanced prostate cancer, com-
`pared mitoxantrone 12 mg/m2 every 3 weeks
`with prednisone 5 mg twice daily to either
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`FIGURE 4 Overall Survival Rates. (A) Southwest Oncology Group 9916 Kaplan-Meier estimates of overall survival
`among men with androgen-independent prostate cancer treated with mitoxantrone and prednisone or docetaxel and es-
`tramustine. (B) TAX 327 Kaplan–Meier estimates of the probability of overall survival in the patients treated with do-
`cetaxel plus prednisone in two different schedules versus mitoxantrone and prednisone. Reprinted with permission from
`Petrylak, et al.44
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`docetaxel 30 mg/m2 weekly for 5 of 6 weeks
`or docetaxel 75 mg/m2 every 3 weeks and
`prednisone 5 mg twice daily.45 In all, 1,006
`patients were enrolled and were stratified by
`pain level or performance status. Weekly do-
`cetaxel demonstrated a trend toward improved
`survival but failed to reach statistical signifi-
`cance (median survival: 17.3 months, P ⫽ 0.3).
`The every 3-week schedule of docetaxel
`showed an advantage in median survival when
`compared with mitoxantrone (18.9 versus 16.4
`months, P ⫽ 0.009; Figure 4B). Furthermore,
`the every 3-week docetaxel regimen had a
`significant improvement in pain control, PSA
`response rate, tumor response rate, and quality
`of life. Toxicity in the every 3-week docetaxel
`schedule was a 32% rate of Grade 3 to 4 neu-
`tropenia, and patients treated with this regimen
`suffered more adverse events than the mitox-
`antrone group (26% versus 20%). The weekly
`docetaxel group experienced an adverse event
`rate of 29%, which was higher than the 3-week
`schedule despite Phase II data suggesting similar
`antitumor activity with a concomitant reduc-
`tion in neutropenia.46 Based on these data, the
`US Food and Drug Administration (FDA) ap-
`proved the regimen of docetaxel 75 mg/m2
`every 3 weeks in combination with prednisone
`5 mg orally twice per day for the treatment of
`advanced prostate cancer.
`
`THE STATUS OF ESTRAMUSTINE IN 2005
`
`Based on preclinical data, estramustine has
`been considered to be an important component
`of taxane-based regimens for prostate cancer.
`Several Phase II trials demonstrated a superior
`response to estramustine plus docetaxel versus
`docetaxel alone as measured by both PSA re-
`sponse and objective soft-tissue response (Table
`1).36-43,47 Although the patient populations en-
`rolled on SWOG 9916 and TAX 327 are not
`exactly the same, general comparisons can be
`made about the efficacy and toxicities of the
`regimens. Estramustine and docetaxel in SWOG
`9916 had similar efficacy to docetaxel and pred-
`nisone in TAX 327. Toxicities between the
`trials were markedly different. The main side
`
`effects of estramustine have been well docu-
`mented; nausea, vomiting, and thrombosis sec-
`ondary to the high estrogen content of
`estramustine are common.36-43,47 In SWOG
`9916, 20% of patients suffered Grade 3 or greater
`nausea and vomiting on the D/E arm. In TAX
`327, there was no nausea and vomiting of Grade
`3 or greater reported. Similarly, in SWOG 9916,
`15% of patients suffered Grade 3 or higher car-
`diovascular or clotting adverse events, but there
`were none of these events in the patients treated
`with docetaxel in TAX 327. These data suggest
`that estramustine was the factor causing the car-
`diovascular and gastrointestinal toxicity and did
`not add significantly to the efficacy of docetaxel.
`Thus, it appears that the use of estramustine with
`docetaxel in advanced prostate cancer is not nec-
`essary and may be detrimental.
`
`PALLIATIVE CHEMOTHERAPY
`
`While docetaxel has become the standard first-
`line therapy for hormone refractory prostate
`cancer, mitoxantrone plus prednisone remains a
`useful regimen in this disease. This combination
`has significant palliative activity in patients expe-
`riencing pain from advanced prostate cancer.
`Tannock, et al.48 demonstrated that the percent-
`age of patients achieving pain relief or having
`declines in analgesic consumption was substan-
`tially greater in those receiving mitoxantrone
`compared with those treated with prednisone
`alone. This observation was confirmed by an-
`other Phase III trial conducted by Kantoff and
`colleagues of the Cancer and Leukemia Group
`B.49 These studies demonstrated that approxi-
`mately one-third of patients receiving mitox-
`antrone chemotherapy demonstrated significant
`pain relief for an average of 8 months. Mitox-
`antrone is FDA-approved and is given as 12 to 14
`mg/m2 intravenously every 3 weeks with 10 mg
`of prednisone or the equivalent hydrocortisone
`dose given orally daily. Currently, it is unclear
`how the effectiveness of mitoxantrone is affected
`when it is used as a second-line agent after do-
`cetaxel compared with the results seen in first-line
`studies.
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`LOCAL AND SYSTEMIC RADIATION FOR PALLIATION
`
`Radiation therapy has long been known to
`provide effective palliation for patients with
`advanced prostate cancer. For patients with
`single sites of osseous pain or with limited
`obstructing masses or lymph nodes, external-
`beam radiation has been demonstrated to be
`very effective in controlling progressive disease.
`For patients with multiple sites of bone in-
`volvement and pain, systemic radioisotopes ad-
`ministered
`intravenously
`have
`significant
`therapeutic effects. The two most commonly
`used radioisotopes
`are
`strontium-89 and
`samarium-153. These isotopes have significant
`differences in physical half-life and particle en-
`ergy, which result in differing side effect pro-
`files. In a Phase III trial, Porter and colleagues
`demonstrated that strontium was more effec-
`tive than placebo in the control of painful
`metastases when given as an adjunct to local
`radiation.50 Although no significant differences
`in survival or in relief of pain at the index site
`were noted, intake of analgesics over time dem-
`onstrated a significant reduction in the arm
`treated with strontium-89 and progression of pain
`(as measured by sites of new pain or the require-
`ment for radiotherapy) and quality of life showed
`statistically significant differences
`in favor of
`strontium-89. These data demonstrate the effec-
`tiveness of strontium. Unfortunately, strontium
`has a long half-life of almost 60 days in bone and
`can lead to decreased blood counts, especially
`affecting platelets. This makes strontium difficult
`to give in a setting where patients are also eligible
`for chemotherapy.
`Samarium, by contrast, can be given with
`minimal marrow toxicity. Sartor and colleagues
`conducted a Phase III trial using samarium and
`demonstrated that a 1 mCi/kg dose was more
`effective than placebo in controlling pain second-
`ary to bone metastases.51 Mild, transient bone
`marrow suppression was the only adverse event
`associated with samarium administration. The
`mean nadir white blood cell (WBC) and platelet
`counts at 3 to 4 weeks after treatment were
`3,800/␮L and 127,000/␮L, respectively. Counts
`recovered to baseline after approximately 8
`weeks. No Grade 4 decreases in either platelets or
`white bloods cells were documented. These find-
`
`ings demonstrate that samarium is both safe and
`effective for the palliation of painful bone metas-
`tases in patients with hormone-refractory prostate
`cancer and suggest that it may be considered for
`integration with chemotherapy regimens.
`The combination of radioisotopes with che-
`motherapy may lead to increased effectiveness
`when compared with either type of agent alone
`in the treatment of bone metastases.52,53 NCI-
`3410 is a Phase III trial to compare the effec-
`tiveness of chemotherapy with or without
`strontium-89 in treating patients who have
`prostate cancer that has spread to the bone.54
`Patients receive one of two chemotherapy reg-
`imens for 6 weeks. Treatment may be repeated
`every 8 weeks for up to two courses. Patients
`are then randomly assigned to one of two
`groups. Patients in Group 1 receive a 24-hour
`continuous infusion of doxorubicin once a
`week for 6 weeks plus
`an infusion of
`strontium-89 at the beginning of chemother-
`apy. Patients in Group 2 receive doxorubicin
`alone. Enrollment to this trial is ongoing.
`
`BISPHOSPHONATE THERAPY
`
`The production of an osteoblastic metastasis in
`prostate cancer is the result of a complex interac-
`tion between prostate tumor cells, osteoclasts, and
`osteoblasts. Before the osteoblasts are activated,
`osteoclasts first break down the bone and initiate
`bone remodeling. Bisphosphonates are analogs of
`pyrophosphate, a normal constituent of the bone
`matrix. These agents bind to bone surfaces (hy-
`droxyapatite crystals), making them less available
`to osteoclast resorption. Additionally, bisphos-
`phonates inhibit recruitment of osteoclast pre-
`cursors, prevent
`the migration of osteoclasts
`toward bone, and inhibit
`the production of
`prostaglandin-E2, interleukin-1, and proteolytic
`enzymes. In a placebo-controlled randomized
`clinical trial, zoledronic acid 4 mg via a 15-
`minute infusion every 3 weeks for 15 months
`reduced the incidence of skeletal-related events
`(SREs) in men with hormone-refractory meta-
`static prostate cancer.55,56 Among 122 patients
`who completed a total of 24 months on study,
`fewer patients in the 4-mg zoledronic acid group
`than in the placebo group had at least one SRE
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`CA Cancer J Clin 2005;55:300–318
`
`(38% versus 49%, P ⫽ 0.028). The annual inci-
`dence of SREs was 0.77 for the 4-mg zoledronic
`acid group versus 1.47 for the placebo group
`(P ⫽ 0.005). The median time to the first SRE
`was 488 days for the 4-mg zoledronic acid group
`versus 321 days for the placebo group (P ⫽
`0.009). Compared with placebo, 4 mg of
`zoledronic acid reduced the ongoing risk of SREs
`by 36% (risk ratio ⫽ 0.64, 95% CI ⫽ 0.485 to
`0.845; P ⫽ 0.002). The investigators concluded
`that long-term treatment with 4 mg of zoledronic
`acid is safe and provides sustained clinical benefits
`for men with metastatic hormone-refractory
`prostate cancer. Based on these data, this agent has
`been approved for the treatment of men with
`bone metastases who have failed hormonal ther-
`apy. Although generally considered safe, serum
`creatinine must be monitored and recent evi-
`dence has linked bisphosphonate use with osteo-
`necrosis of
`the mandible in a minority of
`patients.57,58 It may be prudent
`for patients
`started on zoledronic acid to have a dental exam
`before initiating therapy and patients should be
`regularly asked about their dental health.
`
`A SUGGESTED PARADIGM OF CURRENT
`PRACTICE GUIDELINES
`
`Patients with androgen-independent pros-
`tate cancer fall
`into three broad categories:
`biochemical-only disease, asymptomatic disease
`with positive scans, and symptomatic disease
`(Figure 5). The variability of the natural history
`of the disease in these categories raises several
`major questions: who should be treated, when
`should they be treated, and how should they be
`treated? A patient with a rising PSA despite hor-
`monal therapy should undergo staging with a
`physical exam, bone scan, and computed tomog-
`raphy scan of the abdomen/pelvis. If they have
`biochemical-only disease, a decision must be
`made as to whether to treat these patients or to
`follow them. This first decision can be based, at
`least partially, on the speed at which the PSA is
`doubling (PSADT) as well as other factors such as
`patient age and overall health. Patients with slow
`doubling times (ⱖ8 to 12 months) are suitable for
`monitoring. Bone scans can be performed every
`six months or on a yearly basis. Patients with
`
`rapid PSADT (ⱕ6 to 8 months) should be con-
`sidered for clinical trials.
`One common presentation is the patient
`who is asymptomatic with a rising PSA and a
`positive bone scan. These patients should be
`considered for a clinical trial. Patients in this
`category are eligible to receive docetaxel; how-
`ever, there are no set criteria as to when to treat
`these patients. Many physicians and patients
`choose to wait to start docetaxel until symp-
`toms have developed. Patients with visceral
`disease with or without bone disease are more
`likely to be started on cytotoxic chemotherapy
`while still asymptomatic than are those with
`bone-only disease. The utility of
`starting
`chemotherapy in asymptomatic patients has
`not been proven. Few would now question
`that patients with symptomatic androgen-
`independent prostate cancer (AIPC) should be
`offered chemotherapy as a treatment option.
`Docetaxel
`is considered to be the first-line
`agent of choice. Mitoxantrone, however, has a
`proven palliative benefit in patients with symp-
`toms and can be considered as a first-line agent
`in patients who may not tolerate docetaxel. Of
`note, mitoxantrone is approved for use in pa-
`tients with symptomatic prostate cancer and has
`no proven benefit in asymptomatic patients.
`Because neither of these agents is curative,
`clinical trials for these patients should always
`be considered. Symptomatic patients with sites
`of pain secondary to bone lesions should be
`considered for palliative radiation therapy.
`Zoledronic acid is approved for use in patients
`with bone metastases who have failed hor-
`monal therapy. The question of when to initi-
`ate therapy with this agent has not yet been
`fully answered. Symptomatic patients appear to
`have some benefit with improvement in pain,
`but the real utility may be in the prevention or
`delay of skeletal related events. Systemic radio-
`isotopes have proven palliative benefit in pa-
`tients with multiple sites of bone disease but
`should not be used prophylactically.
`Patients with a known history of prostate
`cancer who present with back pain are best
`treated for impending spinal cord compression as
`a medical emergency until proven otherwise.59-62
`Pain is the presenting symptom in 90% of spinal
`cord compression patients and usually precedes
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`Advances in Prostate Cancer Chemotherapy
`
`FIGURE 5 A Suggested Paradigm of Current Practice Guidelines for Androgen-Independent Prostate Cancer. Patients w