U R O L O G I C O N C O L O G Y
`
`Current management
`of castrate-resistant
`prostate cancer
`
`S.J. Hotte Md MSC* and F. Saad Md†
`
`ABSTRACT
`Prostate cancer (pca) is the most frequently diagnosed
`cancer in North America. Castrate-resistant pca pres-
`ents a spectrum of disease ranging from rising psa
`levels in the absence of metastases or symptoms and
`despite androgen-deprivation therapy, to metastases
`and significant debilitation from cancer symptoms.
`Castrate-resistant pca is usually suspected in patients
`with new symptoms on androgen deprivation therapy,
`with a rising psa, or with new evidence of disease on
`bone scans or computed tomography scans. Institu-
`tion of treatment and the choice of systemic or local
`therapy depend on a number of factors. This review
`discusses the various currently available treatments
`for patients with castrate-resistant pca, from second-
`ary hormonal manipulations to options for post-
`docetaxel systemic therapy.
`
`KEY WORDS
`Castrate-resistant prostate cancer, systemic treatment
`
`INTRODUCTION
`1.
`Prostate cancer (pca) is the most frequently diagnosed
`cancer in North America. It is the fourth most com-
`mon cause of cancer death overall and the third most
`common cause of cancer death in men 1. One in four
`men diagnosed with pca eventually dies from the
`disease. Men with pca that has recurred after local
`therapy or that has disseminated distantly usually
`respond to androgen deprivation therapy (adt); how-
`ever, despite this treatment, most patients eventually
`experience disease progression within a median of
`18–24 months 2.
`
`2. DISCUSSION
`2.1 Definition of Castrate-Resistant Prostate Cancer
`
`a continuous rise in serum levels of prostate-specific
`antigen (psa), progression of pre-existing disease, or
`appearance of new metastases.
`Advanced pca has been known by a number of
`names over the years, including hormone-resistant pca
`(hrpc) and androgen-insensitive pca. Most recently,
`the terms “castrate-resistant” or “castration-recurrent”
`pca were introduced with the realization that intracrine
`and paracrine androgen production plays a significant
`role in the resistance of pca cells to testosterone-
`suppression therapy 3.
`In their second publication, the Prostate Cancer
`Working Group (pcwg2) defined crpc as a continuum
`on the basis of whether metastases are detectable
`(clinically or by imaging) and whether serum testos-
`terone is in the castrate range because of a surgical
`orchiectomy or medical therapy 4. The resulting
`clinical-states model can be used to classify patients.
`Within the rising psa states (castrate and non-castrate),
`no detectable (measurable or non-measurable) disease
`has ever been found. Alternatively, in the clinical
`metastases states (castrate and non-castrate), disease
`has to have been detectable at some point in the past,
`regardless of whether it is currently detectable.
`Castrate-resistant pca presents a spectrum of
`disease ranging from rising psa levels without me-
`tastases or symptoms and despite adt, to metastases
`and significant debilitation from cancer symptoms.
`Prognosis is associated with several factors, including
`performance status, presence of bone pain, extent of
`disease on bone scan, and serum levels of alkaline
`phosphatase. Bone metastases will occur in 90% of
`men with crpc and can produce significant morbidity,
`including pain, pathologic fractures, spinal cord com-
`pression, and bone marrow failure. Paraneoplastic
`effects are also common, including anemia, weight
`loss, fatigue, hypercoagulability, and increased sus-
`ceptibility to infection.
`
`2.2 Management of CRPC
`
`Castrate-resistant pca (crpc) is defined by disease
`progression despite androgen-deprivation therapy
`(adt) and may present as one or any combination of
`
`2.2.1 Determination
`Castrate-resistant pca is usually suspected in patients
`with new symptoms on adt, with a rising psa, or with
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`HOTTE and SAAD
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`new evidence of disease on bone scans or computed
`tomography scans. To determine the castrate-resistant
`state and to properly assign a clinical state, it is im-
`perative that patients have a testosterone level drawn.
`If patients are non-castrate, androgen ablation therapy
`should be instituted or maximized. If patients have
`testosterone levels in the castrate range, the diagnosis
`of crpc can be made.
`
`2.2.2 Secondary Hormonal Manipulations
`In patients who develop crpc and who are relatively
`asymptomatic, secondary hormonal treatments
`may be attempted. To date, no study of secondary
`hormonal treatment has shown a benefit in terms of
`survival, but most trials have been smaller and heav-
`ily confounded by future treatments used. In patients
`treated with monotherapy using luteinizing-hormone
`releasing-hormone agonist or in those who have had
`an orchiectomy, total androgen blockade with testos-
`terone antagonists such as bicalutamide can offer psa
`responses in 30%–35% of patients 5,6.
`For patients who have undergone total androgen
`blockade and are showing signs of progression, the
`anti-androgen may be discontinued in an attempt to
`obtain an anti-androgen withdrawal response, which
`can be observed in 20%–30% of patients. Other
`options may include a change to a different anti-
`androgen, such as nilutamide or flutamide, or the use
`of ketoconazole 7. For all these modalities, transient
`psa reductions have been reported in approximately
`30% of patients.
`Because the androgen receptor remains active in
`most patients who have developed castration-resistant
`disease, groups such as the American Society of
`Clinical Oncology (asco), the National Comprehen-
`sive Cancer Network (nccn), Cancer Care Ontario’s
`Program in Evidence-Based Care, and others recom-
`mend that adt should be continued. Consequently,
`most if not all clinical trials of patients with crpc have
`mandated continued adt.
`Novel agents that potently affect the androgen
`axis have recently been developed and have renewed
`the enthusiasm for effective hormonal manipulation.
`A phase iii clinical trial in men with early crpc that
`has recently completed accrual is looking at whether
`survival can be improved with prednisone and abi-
`raterone acetate, a potent and irreversible inhibitor of
`CYP17 (a critical enzyme in androgen biosynthesis),
`as compared with prednisone and placebo 9–11.
`
`2.2.3 Systemic Corticosteroid Therapy
`Corticosteroid therapy with low-dose prednisone or
`dexamethasone may also offer improvements in psa
`values or palliative outcomes in up to 30% of both
`symptomatic and asymptomatic men 8. As a palliative
`measure, prednisone can be used to improve symp-
`toms such as bone pain; it may also exert an anti-
`neoplastic effect on pca cells themselves. The latter
`effect is most likely achieved by inhibition of adrenal
`
`androgen production through negative feedback in-
`hibiting the secretion of adrenocorticotropic hormone.
`Other postulated mechanisms include the modulation
`of cellular growth factors and the downregulation of
`androgen receptor–dependent transcription.
`Several studies have evaluated prednisone ther-
`apy in crpc patients, although most of them address
`the symptomatic patient 12. The psa response rates,
`which are defined as a post-treatment decrease in psa
`of 50% or more from baseline, have varied from 21%
`to 34%. In asymptomatic men, Heng and Chi reported
`a 22.4% response rate to prednisone (defined as a
`50% or greater psa decline) 13. An additional 16.3% of
`patients had a psa decline of less than 50%. In 90% of
`patients, no side effects were documented. Of all psa
`responders, 27% had a time to progression of more
`than 1 year, and 45% did not require chemotherapy
`for the duration of the study.
`
`2.2.4 First-Line Systemic Chemotherapy
`Currently, only crpc patients who have detectable
`macroscopic metastatic disease should receive
`systemic chemotherapy outside of a clinical trial.
`Patients with advanced pca should be referred early
`to a medical oncologist and should optimally receive
`multidisciplinary care to maximize survival and
`optimize quality of life. Because any treatment for
`advanced disease remains palliative, patients with
`advanced pca should be encouraged to participate in
`clinical trials.
`Combined docetaxel (a taxane drug that induces
`polymerization of microtubules and phosphorylation
`of the Bcl-2 protein) and prednisone is currently con-
`sidered the standard of care for men with crpc and
`detectable metastatic disease, based largely on the
`simultaneous publication of two large randomized
`controlled trials comparing this combination with the
`previously established standard of mitoxantrone and
`prednisone 14,15. Tannock et al. 15 randomized 1006
`patients to one of three treatment arms: intravenous
`docetaxel 75 mg/m2 every 3 weeks, intravenous doc-
`etaxel 30 mg/m2 5 times weekly for 5 of 6 weeks, or
`control therapy with mitoxantrone. All patients also
`received oral prednisone 5 mg twice daily. Petrylak et
`al. 14 reported on 666 eligible patients randomized to
`docetaxel–estramustine or mitoxantrone–prednisone.
`In addition to dexamethasone pre-medication, pa-
`tients in the docetaxel arm also received warfarin or
`acetylsalicylic acid as thrombosis prophylaxis during
`the course of the trial. Men in both trials had clinical
`evidence of metastases with or without symptoms
`and had undergone anti-androgen withdrawal re-
`sponse. Overall survival was the primary endpoint
`in both trials.
`Tannock et al. reported improved survival
`with docetaxel (every-3-weeks dosing) compared
`with mitoxantrone–prednisone [median survival:
`18.9 months vs. 16.5 months; hazard ratio (hr): 0.76;
`95% confidence interval (ci): 0.62 to 0.94; two-sided
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`p = 0.009]. No overall survival benefit was observed
`with docetaxel given on the weekly schedule (hr:
`0.91; 95% ci: 0.75 to 1.11; two-sided p = 0.36).
`Petrylak et al. reported longer survival time with
`docetaxel–estramustine combination chemotherapy
`as compared with mitoxantrone (median survival:
`17.5 months vs. 15.6 months; hr: 0.80; 95% ci: 0.67
`to 0.97; two-sided p = 0.02). That trial also reported a
`median progression-free interval of 6.3 months versus
`3.2 months (hr: 0.73; 95% ci: 0.63 to 0.86; two-sided
`p < 0.0001) favouring docetaxel–estramustine over
`mitoxantrone.
`Pain response was assessed in both trials. Signifi-
`cantly more patients treated with docetaxel (every-3-
`weeks dosing) than patients receiving mitoxantrone
`achieved a pain response (35% vs. 22%, p = 0.01). A
`trend toward improved pain response was observed
`with the weekly schedule docetaxel as compared with
`mitoxantrone (31% vs. 22%, p = 0.08).
`Quality-of-life response, defined as a sustained
`16-point or greater improvement from baseline
`on 2 consecutive measurements, was higher with
`every-3-weeks (22% vs. 13%, p = 0.009) or with
`weekly-schedule docetaxel (23% vs. 13%, p = 0.005)
`than with mitoxantrone. In their trial, Petrylak et al.
`reported no difference in patient-reported pain relief
`between the arms and did not assess quality of life. In
`both trials, psa response rates were also statistically
`significantly higher with docetaxel than with mitox-
`antrone. Measurable disease was present in 27% (n =
`412) and 29% (n = 196) of patients in the two trials.
`Objective response rates for every-3-weeks docetaxel
`and mitoxantrone were 12% and 7% respectively. Pet-
`rylak and colleagues reported objective response rates
`of 17% and 11% favouring docetaxel–estramustine
`over mitoxantrone. The differences in objective re-
`sponse rate between the arms were not statistically
`significant in either trial.
`Based on the results of those two trials, it is
`now recommended that, for men with clinical or
`biochemical evidence of progression and evidence
`of metastases, treatment with docetaxel 75 mg/m2
`administered intravenously every 3 weeks with 5 mg
`oral prednisone twice daily should be offered to
`improve overall survival, disease control, symptom
`palliation, and quality of life 16.
`Although patients in the two pivotal trials re-
`ceived up to 10 cycles of treatment if no progression
`and no prohibitive toxicities were noted, duration of
`therapy should be based on an assessment of benefit
`and toxicities. A rising psa should not be the sole
`criterion for progression; assessment of response
`should incorporate clinical and radiographic criteria.
`The pcwg2 recommends a minimum exposure of 12
`weeks for trials in the pre-chemotherapy or first-line
`chemotherapy setting, recognizing that declines in
`serum psa, if they occur, may not do so for several
`weeks and that a robust psa-based surrogate for clini-
`cal benefit has yet to be identified. Further, to avoid
`
`discontinuing a treatment prematurely, pcwg2 sug-
`gests erring on the side of continuing treatment in
`equivocal cases in which there is no clear evidence
`of either progression or clinical deterioration and in
`which patient safety is not compromised. Although
`these recommendations are targeted at clinical trials
`and clinical investigators, they are also likely to be
`of benefit to clinicians 4.
`In the first-line setting, alternative therapies that
`have not demonstrated improvement in overall surviv-
`al but that can provide disease control and palliation
`and improve quality of life include weekly docetaxel
`plus prednisone, and mitoxantrone plus prednisone
`(or hydrocortisone).
`To date, docetaxel-based chemotherapy remains
`the only treatment that has demonstrated an overall
`survival benefit in most men with metastatic crpc
`regardless of whether they are symptomatic or have
`visceral metastases. The timing of docetaxel therapy
`in men with evidence of metastases but without
`symptoms should be discussed with patients and
`be individualized based on their clinical status and
`preferences. In both the TAX 327 and Southwest On-
`cology Group 9916 trials, the men enrolled continued
`on gonadal androgen suppression and discontinued
`the use of anti-androgens. These maneuvers are
`recommended for men with hrpc who receive che-
`motherapy. Men with hrpc should receive treatment
`to optimize symptom control. Use of estramustine in
`combination with other cytotoxic agents is not rec-
`ommended because of the increased risk of clinically
`important toxicities without evidence of improved
`survival or palliation 16.
`Patients with high-grade disease (Gleason 9–10)
`nonresponsive to first-line adt and patients that prog-
`ress clinically or radiologically without significant psa
`elevations may have neuroendocrine (small-cell) dif-
`ferentiation. The nccn guideline suggests that biopsy
`of accessible lesions should be considered to identify
`these patients, who should then be treated with com-
`bination chemotherapy such as cisplatin–etoposide
`or carboplatin–etoposide 17.
`
`2.2.5 Immunotherapy
`In April 2010, sipuleucel-T became the first immuno-
`therapeutic agent to approved by the U.S. Food and
`Drug Administration for pca, based on consistent ob-
`served improvements in overall survival. Sipuleucel-T
`is an autologous “vaccine” that requires collection of
`white blood cells from individual patients to obtain
`antigen-presenting cells. These antigen-presenting
`cells are then exposed to the prostatic acid phos-
`phatase/granulocyte–macrophage colony–stimulating
`factor fusion protein and re-infused into the patient.
`Patients entered into the studies of sipuleucel-T
`have had excellent to good performance status
`(Eastern Cooperative Oncology Group 0–1), have
`been asymptomatic or very minimally symptomatic,
`and have not had visceral metastases. Although no
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`differences were observed in any trial for clinical
`parameters such as decline in psa, tumour regres-
`sion, or time to progression, improvements in overall
`survival were noted in the integrated analysis of
`D9901 and D9902A, which demonstrated a 33%
`reduction in the risk of death (hr: 1.50; 95% ci: 1.10
`to 2.05; log-rank p = 0.011) 18. The treatment effect
`remained strong after adjustments for imbalances in
`baseline prognostic factors, post-study use of treat-
`ment chemotherapy, and deaths not related to pca.
`The Food and Drug Administration approval was
`finally granted when the confirmatory trial D9902B
`that randomized 512 patients to sipuleucel-T or pla-
`cebo in a 2:1 ratio also found a 22.5% improvement
`in mortality risk (median survival: 25.8 months vs.
`21.7 months; hr: 0.775; 95% ci: 0.614 to 0.979; p =
`0.032) 19. Treatment with sipuleucel-T appears to
`be well tolerated; the most common complications
`include mild-to-moderate chills, pyrexia, and head-
`aches, which are transient.
`
`2.2.6 Second-Line Systemic Chemotherapy
`Unfortunately, no treatment has been shown to
`improve survival or quality of life in patients who
`have progressed on or soon after docetaxel-based
`chemotherapy. Participation in a clinical trial should
`be encouraged.
`Currently, mitoxantrone can be considered de facto
`second-line chemotherapy, but published series sug-
`gest that it has limited activity and increased toxicity
`in that setting, with response rates from retrospective
`series ranging from 9% to 20% 20–22. Mitoxantrone
`has been used as the standard treatment in least two
`published randomized trials 23,24. In the first trial, mi-
`toxantrone induced a psa response in 20% of patients,
`with a median treatment duration of 2.3 months, a
`63% rate of grades 3 and 4 neutropenia, and a median
`survival of 9.8 months. In the second trial, the median
`number of cycles delivered was 2, and time to progres-
`sion was 1.1 months. No psa responses were seen, and
`the rate of grades 3 and 4 febrile neutropenia was 31%.
`Based on those results, mitoxantrone appears to have
`limited benefit, with clear toxicity and questionable
`palliative benefit post docetaxel. It should likely be
`reserved for symptomatic patients for whom clinical
`trials are not an option.
`For patients who have not demonstrated defini-
`tive evidence of resistance to docetaxel, re-treatment
`with this agent can be considered 25–28. In published
`reports of highly selected individuals who had shown
`previous sensitivity to docetaxel, psa declines of at
`least 50% were observed in 32%–45% of patients.
`Eymard and colleagues recently published a mul-
`ticentre retrospective series 28. Of the 148 patients
`who responded to first-line docetaxel, 50 received
`further therapy with docetaxel and were analyzed.
`The median response duration to first-line docetaxel
`was 10.3 months (range: 4.6–45.7 months), and the
`median docetaxel-free interval was 18.4 months
`
`(range: 5.0–46.7 months). Docetaxel was reintro-
`duced as second-line therapy in 52% of patients and as
`further lines in 48%. After docetaxel reintroduction,
`24 patients (48%) had a 50% decline in psa (95% ci:
`34.1% to 61.8%). The median overall survival from
`docetaxel reintroduction was 16 months (95% ci: 13
`to 20 months). In most patients, docetaxel appeared to
`be well tolerated, with a grades 3 and 4 hematologic
`toxicity rate of 6%.
`Cabazitaxel is a potent taxane agent that has
`been selected in preclinical studies by virtue of its
`high cytotoxicity and low affinity for the adenosine
`triphosphate–dependent drug efflux pump P-glyco-
`protein 1, which can be responsible for resistance to
`docetaxel 29. Results from a large phase iii trial evalu-
`ating the efficacy of cabazitaxel were recently pre-
`sented at the asco Genitourinary Cancers Symposium
`in March 2010 30. This randomized placebo-controlled
`trial recruited 755 docetaxel-pretreated crpc patients.
`Overall survival was the primary endpoint of the study,
`and psa response, progression-free survival, response
`rate according to the Response Evaluation Criteria
`in Solid Tumors, and pain response were secondary
`endpoints. Patients were randomized to receive pred-
`nisone 10 mg daily with either 3-weekly mitoxantrone
`12 mg/m2 or cabazitaxel 25 mg/m2. Treatment caused
`a high rate of grades 3 and 4 neutropenia, which was
`observed in 81.7% of patients in the cabazitaxel arm
`and in 58.0% of patients in the mitoxantrone arm,
`with febrile neutropenia incidences of 7.5% and 1.3%
`respectively. Results relating to pain response and to
`quality of life were not reported. A statistically sig-
`nificant and clinically relevant advantage in survival
`emerged in favour of the cabazitaxel group, with a
`median survival of 15.1 months compared with 12.7
`months in the mitoxantrone group (hr: 0.70; 95% ci:
`0.59 to 0.83; p < 0.0001). In light of those positive
`results, cabazitaxel may soon play a prominent role
`as second-line treatment in crpc patients.
`
`2.2.7 Palliative Radiation
`The main source of morbidity for men with crpc is
`the pain associated with bone metastases. Narcotics
`and co-analgesics may help to improve or maintain
`quality of life, but in many cases, radiation therapy
`can be used for optimal palliation. The bone metas-
`tases from pca are often radiosensitive, and most men
`will experience partial or complete pain relief with
`radiation to a specific lesion. Studies have shown that
`a single fraction is as effective as 5 fractions in provid-
`ing palliation 31, but more patients receiving a single
`fraction require re-treatment for pain recurrence.
`In some patients with diffuse bone pain, radioiso-
`topes can be considered. Because of the potential for
`marrow suppression with radioisotopes, adequate blood
`counts are required to initiate treatment. The two main
`isotopes used are strontium and samarium. The main
`advantage of samarium over strontium is its shorter
`scatter, which causes less marrow suppression.
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`2.3 Bone-Targeted Therapy
`
`Bone loss in patients with pca may be a result of the dis-
`ease itself (which is a risk factor for osteoporosis) and of
`therapy with adt 32,33. Bone loss associated with adt has
`been shown to increase the risk of fracture 34. Moreover,
`approximately 70% of patients with advanced pca will
`develop bone metastases, which cause local decreases
`in bone integrity. All of these disease-associated fac-
`tors lead to a fragile bone state and a significant risk of
`skeletal complications, including pathologic fractures,
`debilitating bone pain, and spinal cord compression. The
`patient’s quality of life will likely be affected by these
`complications 35. Radiation or radioisotope therapy and
`bisphosphonates are palliative treatments for patients
`with bone metastases. Bisphosphonates are inhibitors
`of osteoclast-mediated bone resorption that can prevent
`bone loss in patients with pca receiving adt; in that set-
`ting, they can increase bone mineral density 36,37.
`In men with castration-recurrent pca and bone
`metastases, intravenous zoledronic acid (4 mg) every
`3–4 weeks is recommended to prevent disease-related
`skeletal complications, including pathologic frac-
`tures, spinal cord compression, surgery, or radiation
`therapy to bone 38.
`To reduce the risk of adverse effects on renal
`function, the infusion time for zoledronic acid should
`be no less than 15 minutes. Serum creatinine moni-
`toring is suggested before each dose. Results from
`a randomized study 38 showed that skeletal-related
`events occurred less often in men receiving zoledronic
`acid than in men in a placebo group (38% vs. 49%,
`p = 0.02). Zoledronic acid also increased the median
`time to first skeletal-related event (488 days vs. 321
`days, p = 0.01). In treated patients, the rate of skeletal-
`related events showed an overall 36% reduction.
`Zoledronic acid should be initiated at reduced
`dose in men with impaired renal function (estimated
`creatinine clearance: 30–60 mL/min). Treatment is
`not recommended for men with a baseline creatinine
`clearance below 30 mL/min 39. The optimal duration
`of zoledronic acid in men with castration-recurrent
`pca and bone metastases is undefined. Zoledronic
`acid and other bisphosphonates are associated with
`increased risk of osteonecrosis of the jaw (onj) 40–42.
`Most—but not all—patients who develop onj have
`pre-existing dental problems. Excellent oral hygiene,
`baseline dental evaluation for high-risk individuals,
`and avoidance of invasive dental surgery during
`therapy are recommended to reduce the risk of onj.
`In clinical trials, zoledronic acid has been used
`safely with a variety of cytotoxic chemotherapies;
`preclinical data suggest that docetaxel and zole-
`dronic acid may have additive or synergistic effects
`on pca cells 43. Adverse events reported during
`bisphosphonate treatment did not appear to increase
`with concomitant chemotherapy.
`Based on the available evidence, several guide-
`lines—including those of the nccn, the European
`
`Association of Urology, and the International Con-
`sultation on Urological Diseases—recommend that
`bisphosphonates be used to preserve bone health and
`to prevent skeletal complications in patients with
`bone metastases from crpc whether asymptomatic or
`symptomatic. Other bisphosphonates have not been
`shown to be effective for the prevention of disease-
`related skeletal complications.
`Other bone-targeted agents include denosumab,
`an inhibitor of receptor activator for nuclear factor
`κB ligand 44, which has been shown to be effective
`in preventing bone loss attributable to adt 45. The
`same agent is currently being studied in the setting
`of prevention of bone metastases in high-risk patients
`and also in the prevention of skeletal-related events
`in patients with bone metastases.
`
`2.4 Clinical Trials and Future Directions
`
`Men with crpc are living longer and with improved
`quality of life, but most, if not all, eventually succumb
`to their disease. Better treatments are required.
`A phase iii study of abiraterone–prednisone com-
`pared with prednisone–placebo in men who progressed
`after docetaxel has recently completed accrual. The
`results of that trial are widely anticipated. Many other
`studies are ongoing or planned. Several trials focus
`on adding a second agent to docetaxel in the first-line
`setting. Other agents are also under investigation to
`determine their role in the pre-chemotherapy setting.
`A number of trials in patients who received previous
`treatment with docetaxel are evaluating novel anti-
`androgens, novel cytotoxic agents, and novel targeted
`therapies. Because crpc remains an incurable and
`ultimately fatal illness, participation in clinical trials
`at all stages of the disease remains paramount.
`
`3. SUMMARY
`The multifaceted problem of crpc needs a multidis-
`ciplinary approach (Figure 1). Many aspects of the
`disease—biological, chronological, physical, and
`psychological—need to be taken into account when
`deciding on treatment. All specialties involved in the
`management of crpc need to be aware that hormone
`therapy diminishes bone health, chemotherapy with
`docetaxel can provide a survival benefit, and zole-
`dronic acid reduces and delays skeletal complications.
`Building on those positive results is necessary to
`further improve survival, symptom management, and
`quality of life in these poor-prognosis patients.
`
`4. CONFLICT OF INTEREST DISCLOSURES
`FS is an advisor and has conducted research with
`Novartis, Sanofi Aventis, Amgen. SJH has acted as
`an advisor and has conducted research with Novartis
`and Sanofi Aventis. No financial support was given
`for the work in preparing this article.
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`figure 1 proposed approach for patients with castrate-resistant prostate cancer. pSa = prostate-specific antigen; prn = as needed;
`pSadt = prostate-specific antigen doubling time; metS = metastases. a In castrate-resistant prostate cancer, clinical trials should be considered
`whenever possible.
`
`5. REFERENCES
` 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA
`Cancer J Clin 2008;58:71–96.
` 2. Sharifi N, Dahut WL, Steinberg SM, et al. A retrospective study
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