`Characterising the castration-resistant prostate
`cancer population: a systematic review
`
`M. Kirby,1 C. Hirst,2 E. D. Crawford3
`
`Review Criteria
`Observational studies reporting epidemiological
`data on CRPC were identified through systematic
`searches of literature on PubMed, Embase and
`authors own databases. Articles were selected
`using predefined inclusion ⁄ exclusion criteria, and
`data were abstracted in a structured manner.
`Where possible and appropriate, meta-analysis of
`data was performed to provide pooled weighted
`means.
`
`Message for the Clinic
`This review of real-world evidence demonstrates
`that CRPC is a common and highly morbid
`progression of prostate cancer, with around 10–
`20% of prostate cancer patients progressing to this
`state within 5 years. Metastases are present in over
`84% of CRPC patients, and the mean survival is
`around 14 months from CRPC diagnosis. Bone pain
`occurs in most patients, and fractures, spinal cord
`compression and vertebral collapse are common.
`Variability in definitions and clinical practice hinder
`the comparison of research, and efforts should be
`made to improve consistency in future research.
`
`1The Prostate Centre, London,
`UK
`2Global Epidemiology,
`AstraZeneca R&D, Alderley, UK
`3University of Colorado Health
`Science Center, Denver, CO,
`USA
`
`Correspondence to:
`Professor Mike Kirby,
`30 Wedon Way, Bygrave,
`Baldock, Herts SG7 5DX
`Tel: + 44 (0) 1462 892234
`Email: kirbym@globalnet.co.uk
`
`Disclosures
`Professor Kirby has received
`funding for research, advice,
`lecturing and conference costs
`from the pharmaceutical
`industry. Dr Hirst is currently an
`employee of AstraZeneca R&D
`UK, and has previously worked
`as a consultant in epidemiology
`for several pharmaceutical
`companies. Professor Crawford
`has served as a consultant and
`speaker for GlaxoSmithKline,
`Sanofi-Aventis and AstraZeneca.
`
`S U M M A R Y
`
`Background: Castration-resistant prostate cancer (CRPC) is an advanced form of
`prostate cancer associated with poor survival rates. However, characterisation of
`the disease epidemiology is hampered by use of varying terminology, definition
`and disease management. The aim of this review was to conduct a systematic
`review to provide greater clarity on the sum of the available epidemiologic evi-
`dence and to guide future research into the disease prevalence, progression, char-
`acteristics and outcome. Methods: Systematic searches of PubMed and Embase
`were performed in March 2010 to identify relevant observational studies relating
`to the epidemiology, progression and outcomes of CRPC. Further studies were
`identified for inclusion in our review through manual searches of the authors’ bib-
`liographical databases and the reference lists of the included articles. Results: We
`identified 12 articles (10 full papers and 2 abstracts)
`reporting studies that
`included a total of 71,179 patients observed for up to 12 years for evaluation in
`our review. Five studies looked at the prevalence of CRPC in patients with prostate
`cancer. Together,
`the data indicate that 10–20% of prostate cancer patients
`develop CRPC within approximately 5 years of follow-up. Two studies reported the
`prevalence of bone metastases present at diagnosis of CRPC. Together, ‡ 84%
`were shown to have metastases at diagnosis. Of those patients with no metasta-
`ses present at diagnosis of CRPC, 33% could expect to develop them within
`2 years. The median survival of patients with CRPC was reported in five studies,
`with values varying from 9 to 30 months. A pooled, sample-weighted survival esti-
`mate calculated from the survival data included in this review is 14 months. Very
`few studies that met our inclusion criteria evaluated treatment patterns in CRPC.
`One study reported that only 37% of patients with CRPC received chemotherapy,
`with the remainder receiving only steroids and supportive care. The most common
`palliative therapies administered to patients with skeletal symptoms were radio-
`therapy,
`radionuclide therapy, bisphosphonates and opioids. Conclusions: This
`review highlights the poor prognosis of patients with CRPC, and demonstrates a sur-
`vival of 9–13 months in those patients with metastatic CRPC. Furthermore, progres-
`sion to CRPC is associated with deterioration in quality of life, and few therapeutic
`options are currently available to patients with CRPC. However, epidemiologic study
`of these patients is hampered by differing terminology, definitions and treatment
`paradigms. Our review highlights the need for further well-designed, epidemiological
`studies of CRPC, using standardised definitions and methods.
`
`Introduction
`
`Cancer of the prostate is the most common cancer
`occurring in the men of the USA and Europe (1,2).
`In the minority of patients whose cancers are aggres-
`sive or advanced, therapeutic options include prosta-
`tectomy, radiation therapy and, more commonly,
`
`androgen-deprivation therapy (3). Castration-resis-
`tant prostate cancer (CRPC) is an advanced form of
`prostate cancer characterised by disease progression
`following
`surgical or pharmaceutical
`(androgen
`deprivation) castration. The process by which pros-
`tate cancer cells become castrate resistant is unclear,
`but it has been proposed that androgen ablation pro-
`
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`1181
`
`vides a selective advantage to androgen-independent
`cells, which grow and eventually repopulate the
`tumour (4). Compared with castration-sensitive pros-
`tate cancer, the prognosis for patients with CRPC is
`poor and survival is reduced. Treatment options have,
`until very recently, been limited mainly to symptom-
`atic relief of bone metastases, which are more common
`in CRPC than in castration-sensitive disease (5–8).
`Defining epidemiological parameters of disease is
`an essential component of understanding how, when
`and where the disease develops; knowledge of the
`natural history of the disease and the likely out-
`comes of disease enable effective targeting and devel-
`opment of treatments. To give a clear picture of the
`burden of CRPC, one must take into account the
`prevalence of the disease, relative timing of onset in
`relation to prostate cancer diagnosis, characteristics
`of the patients including demographics and comor-
`bidity, onset of metastatic disease, and likely sur-
`vival. There is, however, a paucity of epidemiological
`evidence specifically characterising CRPC outside of
`controlled trial settings in which patients may not
`represent the general population and normal disease
`progression. This may result in suboptimal disease
`management; for example, identifying patients with
`CRPC who are at risk of developing metastases is
`currently hindered by poor understanding of
`the
`epidemiology of CRPC.
`Identifying individuals with CRPC may seem
`straightforward to treating physicians, who are
`responsible for managing this progression of the dis-
`ease after castration treatment. Characterising the
`disease in epidemiological terms, for example inci-
`dence, prevalence and survival, is, however, less clear.
`This may be attributed at least in part to the diffi-
`culty in defining, and hence studying, the patient
`population. The varying terminology – CRPC, HRPC
`(hormone refractory), AIPC (androgen independent),
`ERPC (endocrine resistant) – reflect subtle differ-
`ences in definition which may hinder comparison of
`research. Physicians may also use different methods
`in diagnosis: PSA testing, development of metastases
`or other factors may determine whether a patient is
`defined as CRPC. The recently published European
`Association of Urology (EAU) guidelines aim to
`standardise CRPC diagnosis, and include a list of five
`defining factors of CRPC (3). These are:
`• Serum castration levels of testosterone.
`• Three consecutive rises of PSA 2 weeks apart
`resulting in two 50% increases over the nadir.
`• Anti-androgen withdrawal for at least 4 weeks.
`• PSA progression despite
`secondary hormonal
`manipulations.
`• Progression of osseous or soft tissue lesions.
`
`CRPC is a heterogeneous disease, and despite the
`availability of such practical guides to diagnose CRPC,
`in practice, this may vary. Furthermore, treatment
`pathways and clinical practice, in particular, the stage
`in the disease at which androgen-deprivation therapy
`is initiated, vary markedly between geographical loca-
`tions and even individual clinics. Therefore, establish-
`ing common epidemiological estimates for the CRPC
`population becomes highly complex and risks becom-
`ing less relevant to individual scenarios.
`The aim of this review was to improve the clarity
`of epidemiological evidence around CRPC, by sys-
`tematically identifying, evaluating and describing the
`most relevant studies that characterise the CRPC
`patient population using observational data. From
`this, we aim to provide clearer guidance on measure-
`ment of epidemiological estimates of disease preva-
`lence, progression and outcome, and to guide future
`research into CRPC.
`
`Methods
`
`PubMed and Embase searches were performed in
`March 2010 using the search terms detailed in
`Figure 1. Searches were limited to journal articles
`published in the previous 10 years reporting studies
`in men. Observational epidemiological studies were
`sought, as they were considered the best source of
`real-world non-interventional data on disease epide-
`miology, and randomised controlled trials,
`in vitro
`studies, editorials, letters, practice guidelines, reviews,
`case reports and comments, were excluded.
`Relevant articles were screened, first, on the basis
`of the title and then on the abstract as outlined in
`Figure 1. Articles were then further screened based
`on the full text, and those that explored the epidemi-
`ology,
`time course and outcomes of CRPC were
`selected.
`Further studies were identified for inclusion in our
`review through manual searches of the authors’ bib-
`liographical databases and the reference lists of the
`included articles.
`The definition of CRPC, prevalence, metastatic sta-
`tus and survival of patients with CRPC were evalu-
`ated for each of the included studies, and symptoms,
`quality of
`life, and treatment patterns were also
`described if reported in the studies. Where possible,
`data were pooled to provide estimates for each of the
`epidemiological parameters.
`
`Results
`
`The PubMed and Embase searches identified 3329
`unique articles. From these, six relevant articles were
`
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`The Epidemiology of CRPC
`
`PubMed and embase* were searched using the following string:
`
`(“prostate cancer” [TI] or “cancer of the prostate” [TI] or
`“prostatic cancer” [TI] or “prostate neoplasm” [TI] or
`"prostatic neoplasms" [TI] or “prostate neoplasia” [TI])
`AND (prevalence [TIAB] or incidence [TIAB] or
`epidemiology [TIAB] or case–control [TIAB] or
`longitudinal [TIAB] or cohort [TIAB])
`
`Unique results: n = 3329
`
`Articles screened based on title
`
`Selected: n = 228
`
`Rejected: n = 3101
`
`Articles screened based on abstract
`
`Selected: n = 51
`
`Rejected: n = 177
`
`Articles screened based on full text
`
`Selected: n = 6
`
`Rejected: n = 45
`
`+ articles from authors’ databases: n = 4
`
`+ articles from reference lists: n = 2
`
`12 articles for inclusion in review
`
`Figure 1 Search strategy. *The search string syntax was adapted for use in Embase
`
`selected. The main reasons for excluding articles were
`a main focus on drug trial data (interventional
`study), the role of gene polymorphisms, the epidemi-
`ology of prostate cancer, in general (not CRPC) or
`the prevalence ⁄ survival ⁄ progression of CRPC
`that
`was not reported. Four further articles were selected
`from the authors’ databases, and two were identified
`through searching of reference lists. This resulted in
`12 articles (10 full papers and 2 abstracts) suitable
`for evaluation in our review.
`
`Definition of CRPC used
`Various diagnostic criteria were used by the 12
`studies
`included in our
`review; none
`exactly
`matched with the EAU guidelines outlined above
`
`(3). Rising PSA levels were used to diagnose
`CRPC in nine (75%) of the studies (9–17). How-
`ever,
`two of
`these also categorised patients who
`had a new lesion on a bone scan or growth of a
`lesion on a computed tomography (CT) scan as
`having CRPC (10,14). Another study relied upon
`observing worsening metastatic lesions by bone or
`CT scan in patients
`receiving hormone therapy
`(18). One study selected patients who had a diag-
`nosis of symptomatic M1 metastatic CRPC using
`the Tumour Node Metastasis (TNM) staging crite-
`ria (19), and the final study assigned CRPC status
`to patients who failed to respond to postcastration
`hormone therapy and were switched to a third-
`line therapy (20).
`
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`1183
`
`The prevalence of CRPC in patients with
`prostate cancer
`Five studies estimated the prevalence of CRPC in
`patients with prostate cancer (Table 1). Four of these
`evaluated patients were those who had been recently
`diagnosed with prostate cancer (9–11,20); the fifth
`study investigated patients with prostate cancer, who
`had undergone radical prostatectomy (12).
`A statistical, propensity score algorithm was used
`by Alemayehu et al. to identify patients with CRPC
`from a pool of prostate cancer patients identified
`from a large US medical claims database (10). Dur-
`ing
`a
`6-year
`period,
`15,361
`hormone-treated
`patients (aged 40 years or over) were diagnosed
`with prostate cancer.
`In the same period, 2740
`developed CRPC, which suggests a prevalence of
`17.8%. The largest study of CRPC conducted to
`date used another US claims database, MarketScan
`(20). In total, 44,791 medically or surgically cas-
`trated adult prostate cancer patients were followed
`up until
`their exit
`from the database. Of
`these,
`4266 (9.5%) developed CRPC (mean follow-up of
`approximately 2.1 years per patient). A similar
`study was conducted using data from UK primary
`care patients recorded in The Health Improvement
`Network (THIN) database (11). The data reveal
`that,
`in a 5-year period, 8678 patients
`aged
`40 years or over were diagnosed with prostate
`cancer. Of these, 969 developed CRPC, a prevalence
`of 11.2%.
`An Italian study of 211 secondary care patients
`with prostate cancer demonstrated that, within the
`55 months
`following diagnosis, 53% of patients
`(median age 70 years) were considered to have
`CRPC (10). A further study investigated patients
`with prostate cancer who had undergone radical pro-
`statectomy (12). The authors reported that 19% of
`patients developed CRPC within a median 55-month
`follow-up period.
`As discussed above, the available CRPC definition
`guidelines (3) were not routinely used by the studies
`included in this review. Despite the heterogeneity
`between studies, the results of four of these five differ-
`ent studies suggest that 10–20% of prostate cancer
`patients develop CRPC in approximately 5 years of
`follow-up. It is likely that if similar study populations
`and disease definitions were used, this estimated range
`would be even tighter. The greatest outlier in these
`data came from the study that categorised patients
`who had a new lesion or growth of a lesion on a CT
`scan as having CRPC (10), which probably explains
`why this study estimated a higher prevalence (53%)
`than the studies that characterised CRPC on the basis
`of increasing PSA levels or treatment patterns.
`
`Metastatic CRPC
`Bone scans were used to investigate the prevalence of
`metastases at the time of CRPC diagnosis in two
`small studies (13,14) (Table 2). A Japanese study
`reported that in a population of 151 patients with
`CRPC (defined as three consecutive increases in PSA
`after castration), 84% had bone metastases at diagno-
`sis (13). A separate study conducted in Italy reported
`that, of 200 patients with CRPC, 95% had bone
`lesions at diagnosis; however, as bone lesions were a
`qualifying criterion for CRPC status in the study, this
`may be an overestimate.
`The progression to development of metastases
`was shown in a further paper that evaluated patients
`with CRPC (mean age 73 years) who had no metas-
`tases present at CRPC diagnosis (defined as rising
`PSA levels despite androgen-deprivation therapy)
`(17) (Table 2). Between 1999 and 2002, 201 chemo-
`therapy-naı¨ve CRPC patients, were followed up for
`24 months from CRPC diagnosis. Of those patients
`who had no metastases at CRPC diagnosis, 33%
`had developed one or more (identified by bone
`scanning and radiography) within 2 years of CRPC
`diagnosis.
`
`Survival for patients with CRPC
`The median survival of patients with CRPC was
`reported in five studies (13–16,18). Reported values
`varied from 9 to 30 months (Table 3). Again, there
`was heterogeneity between studies. The individual
`studies did not consistently report the mean patient
`age, and so evaluating the effect of age on survival is
`not possible from these data. The study populations
`also varied in terms of the proportion of patients
`with metastases and bone pain. Another factor affect-
`ing survival that was not comparable between studies
`was the use of chemotherapy. One study did not
`report the percentage of patients who received che-
`motherapy and the values reported by the other four
`studies ranged from 14% to 100%. Radiotherapy use
`was not consistently reported.
`Two studies included the presence of metastatic
`lesions as one of their criteria for defining CRPC
`(15,18), and these studies reported the shortest sur-
`vival estimates. In the first study,
`in which CRPC
`was defined as rising serum PSA concentrations and
`serum alkaline phosphatase activity, progressively
`worsening bone pain or the appearance or re-appear-
`ance of
`skeletal metastases on bone scintigraphy
`despite being androgen deprived, the mean survival
`after the development of CRPC in 84 patients was
`8.6 months (15). The second study of 89 US patients
`with CRPC (mean age 73 years) reported the mean
`survival after the diagnosis of CRPC (defined as
`
`ª 2011 Blackwell Publishing Ltd Int J Clin Pract, November 2011, 65, 11, 1180–1192
`
`WCK1051
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`
`
`
`1184
`
`The Epidemiology of CRPC
`
`undergoneRP
`PCwhohave
`19%ofpatientswith
`
`months
`Median:55(range:1–145)
`
`PCinsecondarycare
`53%ofpatientswith
`
`55months
`Median:
`
`withPC
`11.2%ofpatients
`
`Upto10years
`
`patientswithPC
`9.5%ofcastrate
`
`25months
`fromdatabase,mean
`Followeduntilexit
`
`patientswithPC
`17.8%ofcastrate
`
`Upto6years
`
`increasingtrend
`SerumPSA>0.4ng⁄mlwithan
`alesiononaCTscan
`lesiononabonescanorgrowthof
`duringandrogendeprivation,anew
`twoconsecutiveincreasesinPSA
`Despitecastratelevelsoftestosterone,
`
`ofincreasinglevelsofPSA
`castrationandtemporalevidence
`Arecordofmedicalorsurgical
`orchemotherapy
`toathirdhormonaltherapy
`second-linehormonetreatment
`definedasaswitchfromtheir
`postcastrationhormonetherapy,
`patientswhofailedtorespondto
`CRPCstatuswasassignedto
`scoreofmultiplefactors
`identifiedusingapropensity
`patientswithCRPCwere
`castration.Furthermore,
`followingsurgical⁄medical
`AtleasttwoincreasesinPSA
`
`47–87)years
`Median:70(range:
`
`Italy(1996–2003)
`
`atindexdate
`40yearsormore
`
`wereanalysed)
`1998to2008
`UK(recordsfrom
`
`18–97years
`
`wereanalysed)
`2000to2008
`USA(recordsfrom
`
`atindexdate
`40yearsormore
`
`wereanalysed)
`2001to2007
`USA(recordsfrom
`
`PrevalenceofCRPC
`
`Follow-upperiod
`
`DefinitionofCRPC
`
`Patientage
`
`conducted)
`(yearsstudy
`Country
`
`CRPC,castration-resistantprostatecancer;CT,computedtomography;NR,notreported;PC,prostatecancer;PSA,prostate-specificantigen;RP,radicalprostatectomy.
`
`NR
`
`USA(1990–1999)
`
`undergoneRP
`PCwhohad
`1045patientswith
`
`Bianco(12)
`
`hadRP
`withPCwho
`Patients
`
`insecondarycare
`diagnosedwithPC
`211patientsnewly
`caredatabase
`aUKprimary
`PCusingdatafrom
`8678patientswith
`Retrospectivestudyof
`claimsdatabase
`medicalcare
`identifiedfromaUS
`undergonecastration,
`withPCwhohad
`44,791patients
`Retrospectivestudyof
`
`claimsdatabase
`aUSmedicalcare
`patientswithPCfrom
`datafrom15,361
`Retrospectivestudyof
`
`sample
`Study
`
`Berruti(10)
`
`Morgan(11)
`
`Cabrera(20)
`
`Alemayehu(9)
`
`Reference
`
`withPC
`Patients
`
`Table1TheprevalenceofCRPCinpatientsprostatecancer
`
`ª 2011 Blackwell Publishing Ltd Int J Clin Pract, November 2011, 65, 11, 1180–1192
`
`WCK1051
`Page 5
`
`
`
`The Epidemiology of CRPC
`
`1185
`
`CRPC,castration-resistantprostatecancer;CT,computedtomography;EOD,extentofdisease;NR,notreported;PSA,prostate-specificantigen.
`
`33%at2years
`
`48months
`
`NA
`
`0%
`
`95%hadbonelesions
`definedasEODscore‡1
`Bonemetastasis
`
`37%
`
`metastases
`presenceofbone
`Progressionto
`
`period
`Follow-up
`
`84%
`
`NR
`
`diagnosisofCRPC
`metastasesat
`ofbone
`Prevalence
`
`chemotherapy
`whoreceived
`patients
`Percentageof
`
`therapy
`androgen-deprivation
`RisingPSAdespite
`ofalesiononaCTscan
`onabonescanorgrowth
`deprivation,anewlesion
`inPSAduringandrogen
`Twoconsecutiveincreases
`castration
`undersurgical⁄medical
`anti-androgentherapy
`inPSAaftercombined
`Threeconsecutiveincreases
`
`atstartofstudy
`73(range:66–80)
`
`(1999–2002)
`NR
`
`CRPC
`201patientswith
`
`Smith(17)
`
`73(range:52–92)
`
`(1990–2003)
`Italy
`
`CRPCinsecondarycare
`200patientswith
`
`Berruti(14)
`
`44%wereage70–79
`26%wereage60–69
`
`(1990–2004)
`Japan
`
`ofCRPC
`Definition
`
`(years)
`atCRPCdiagnosis
`Meanage
`
`conducted)
`(yearsstudy
`Country
`
`withCRPC
`151patients
`
`sample
`Study
`
`Inoue(13)
`
`Reference
`
`Table2Prevalenceofbonemetastases
`
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`The Epidemiology of CRPC
`
`diagnosis(n=81)
`withoutbonepainat
`monthsinthose
`comparedwith30
`CRPCwas18months
`painatdiagnosisof
`65patientswithbone
`Mediansurvivalinthe
`
`diagnosisofCRPC
`14.5monthsfrom
`Mediansurvivalwas
`
`diagnosisofCRPC
`0.6–67)from
`13months(range:
`Mediansurvivalwas
`
`ofCRPC
`fromdiagnosis
`8.6±10.6months
`Meansurvivalwas
`
`Survival
`
`NR
`
`andfromCRPCdiagnosis:18months
`initialPCdiagnosis:43months
`Meanfollow-upperiodfrom
`
`37%
`
`14%
`
`(18monthafterlatestenrolment)
`untildeathorlastfollow-up
`FromdocumentationofCRPC
`
`ofCRPCuntildeath
`Fromdocumentation
`
`23%
`
`chemotherapy
`whoreceived
`patients
`Percentageof
`
`NR
`
`period
`Follow-up
`
`castration
`surgical⁄medical
`therapyunder
`anti-androgen
`aftercombined
`increasesinPSA
`Threeconsecutive
`onaCTscan
`growthofalesion
`onabonescanor
`deprivation,anewlesion
`PSAduringandrogen
`consecutiveincreasesin
`testosterone,two
`Despitecastratelevelsof
`
`hormonetherapy
`scanwhilereceiving
`lesionsbyboneorCT
`Worseningmetastatic
`scintigraphy
`metastasesonbone
`activityandappearanceof
`risingalkalinephosphatise
`serumPSAconcentration,
`bonepain,rising
`Progressivelyworsening
`
`44%wereage70–79
`26%wereage60–69
`
`(1990–2004)
`Japan
`
`withCRPC
`151patients
`
`Inoue(13)
`
`73(range:52–92)
`
`(1990–2003)
`Italy
`
`73(range:52–96)
`
`(1994–1999)
`USA
`
`insecondarycare
`200patientswithCRPC
`insecondarycare
`withCRPC
`patients
`cohortof89
`Retrospective
`
`Berruti(14)
`
`Hwang(18)
`
`ª 2011 Blackwell Publishing Ltd Int J Clin Pract, November 2011, 65, 11, 1180–1192
`
`NR
`
`(NR)
`Netherlands
`
`ofCRPC
`Definition
`
`diagnosis(years)
`atCRPC
`Meanage
`
`conducted)
`(yearsstudy
`Country
`
`insecondarycare
`withCRPC
`84patients
`
`sample
`Study
`
`(15)
`Soerdjbalie-Maikoe
`
`Reference
`
`Table3SurvivalinpatientswithCRPC
`
`WCK1051
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`The Epidemiology of CRPC
`
`1187
`
`worsening metastatic lesions while receiving hormone
`therapy) to be 13 months (18).
`The study populations
`investigated by Berruti
`et al. and Inoue et al.
`included patients with and
`without metastases at CRPC diagnosis. Survival esti-
`mates were reported to be 15 and 30 months respec-
`tively (13,14). Inoue et al. reported a positive impact
`of irradiation administered for bone pain on the sur-
`vival estimates in their study. This may go some way
`to explaining their longer survival estimate.
`One of the longest survival estimates (15.9 months
`[range: 12.4–20.5]) was reported by a retrospective
`study of Canadian secondary care patients (median
`age 71 years) (16). This was the only study in which
`all patients had received chemotherapy following
`their CRPC diagnosis, which may indicate a fitter
`population who were able to tolerate chemotherapy.
`A pooled, sample-weighted survival estimate calcu-
`lated from the survival data included in this review
`is 14.0 months.
`
`Symptoms and quality of life in patients
`with CRPC
`Primary symptoms of prostate cancer were not eval-
`uated in any of the studies of CRPC selected for
`inclusion in our review. However, bone pain and
`skeletal events were evaluated in three papers (13–
`15) (Table 4). In the study by Inoue et al., 45% of
`the population were experiencing bone pain at the
`time of CRPC diagnosis (13). This increased to 80%
`during the follow-up period (mean: 18 months). It
`was also reported that 14% of the study population
`experienced bone fractures during the follow-up per-
`iod. Of 200 patients with CRPC (37% of whom
`received chemotherapy) in the study by Berruti et al.,
`89% experienced bone pain during an 18-month fol-
`low-up period (14). Other reported skeletal events
`included vertebral collapse (21%),
`fractures (13%)
`and spinal cord compression (10%). In the study by
`Soerdjbalie-Maikoe et al., the presence of progres-
`sively worsening bone pain was used as one of the
`criteria for diagnosing CRPC (15). Of 84 patients, 19
`(23%) received chemotherapy. The authors reported
`that 24% of
`their patient population developed
`spinal cord compression 3 days to 10 months after
`the establishment of CRPC.
`Health-related quality of life findings for a popula-
`tion of 280 patients with metastatic CRPC (approxi-
`mately 12% of whom received chemotherapy) were
`reported from an observational, multinational cohort
`study (19) (Table 4). Health-related quality of
`life
`was assessed over a 9-month follow-up period using
`the European Organization for Research
`and
`Treatment of Cancer Quality of Life Questionnaire
`(EORTC),
`the Functional Assessment of Cancer
`
`CRPC,castration-resistantprostatecancer;CT,computedtomography;NR,notreported;PSA,prostate-specificantigen.
`
`diagnosis
`followingaCRPC
`fromfirstchemotherapy
`(range:12.4–20.5)months
`Mediansurvivalwas15.9
`
`Survival
`
`100%
`
`UntilFebruary2008
`
`oftestosterone
`despitecastratelevels
`symptomaticprogression
`IncreasingPSAlevelsor
`
`chemotherapy
`whoreceived
`patients
`Percentageof
`
`period
`Follow-up
`
`ofCRPC
`Definition
`
`Median:71years
`
`diagnosis(years)
`atCRPC
`Meanage
`
`2005–June2007)
`(August
`Canada
`
`insecondarycare
`withCRPC
`88patients
`
`conducted)
`(yearsstudy
`Country
`
`sample
`Study
`
`Chin(16)
`
`Reference
`
`Table3Continued
`
`ª 2011 Blackwell Publishing Ltd Int J Clin Pract, November 2011, 65, 11, 1180–1192
`
`WCK1051
`Page 8
`
`
`
`1188
`
`The Epidemiology of CRPC
`
`appetiteloss
`vomiting,dyspnoeaand
`domainswerepain,nauseaand
`thestudyperiod.Themostsensitive
`andsignificantdeteriorationover
`ofthoseinEORTCshowedarapid
`questionnaires,andthemajority
`theFACT-PandtheEQ-5D
`HRQoLsymptomsassessedin
`
`12%
`
`9months
`
`monthsafterdiagnosis
`compression3days–10
`24%developedspinalcord
`
`23%
`
`NR
`
`duringthefollow-upperiod
`89%experiencedbonepain
`follow-upperiod
`bonefracturesduringthe
`bonepainand14%experienced
`diagnosis.80%experienced
`painattimeofCRPC
`45%experiencedbone
`
`Outcome
`
`37%
`
`18months
`
`NR
`
`fromCRPCdiagnosis
`Mean18months
`
`chemotherapy
`received
`patientswho
`Percentageof
`
`period
`Follow-up
`
`byTNMstagingcriteria
`M1metastaticCRPCwas
`Diagnosisofsymptomatic
`onbonescintigraphy
`appearanceofmetastases
`phosphatiseactivityand
`concentration,risingalkaline
`pain,risingserumPSA
`Progressivelyworseningbone
`growthofalesiononaCTscan
`lesiononabonescanor
`androgendeprivation,anew
`increasesinPSAduring
`testosterone,twoconsecutive
`Despitecastratelevelsof
`
`castration
`therapyundersurgical⁄medical
`combinedanti-androgen
`increasesinPSAafter
`Threeconsecutive
`
`FunctionalAssessmentofCancerTherapy-Prostate;HRQoL,health-relatedqualityoflife;NR,notreported;PSA,prostate-specificantigen;TNM,TumourNodeMetastasis.
`CRPC,castration-resistantprostatecancer;CT,computedtomography;EORTC,EuropeanOrganizationforResearchandTreatmentofCancerQualityofLife;EQ-5D,5-dimensionEuroQolquestionnaire;FACT-P,
`
`72years
`
`Multinational(NR)
`
`metastaticCRPC
`280patientswith
`
`Sullivan(19)
`
`NR
`
`TheNetherlands(NR)
`
`73(range:52–92)
`
`Italy(1990–2003)
`
`age70–79
`44%were
`age60–69
`26%were
`
`Japan(1990–2004)
`
`ofCRPC
`Definition
`
`(years)
`atCRPCdiagnosis
`Meanage
`
`conducted)
`(yearsstudy
`Country
`
`secondarycare
`withCRPCin
`84patients
`
`secondarycare
`withCRPCin
`200patients
`
`withCRPC
`151patients
`
`sample
`Study
`
`Soerdjbalie-Maikoe(15)
`
`Berruti(14)
`
`Inoue(13)
`
`Reference
`
`Table4SymptomsandqualityoflifeinpatientswithCRPC
`
`ª 2011 Blackwell Publishing Ltd Int J Clin Pract, November 2011, 65, 11, 1180–1192
`
`WCK1051
`Page 9
`
`
`
`The Epidemiology of CRPC
`
`1189
`
`Therapy-Prostate (FACT-P) and the five-dimension
`EuroQol questionnaire (EQ-5D). The results of the
`study highlighted a rapid and significant deteriora-
`tion in FACT-P and EQ-5D scores and in most items
`evaluated by EORTC during the 9-month observa-
`tion period. The most sensitive domains were pain,
`nausea and vomiting, dyspnoea and appetite loss.
`
`Treatment patterns in CRPC
`Very few of the included observational studies evalu-
`ated treatment patterns
`in CRPC. One
`study
`reported the treatment received by patients with
`CRPC (14) and highlighted the high proportion of
`patients with CRPC who do not receive radical ther-
`apy, which may be because of the limited options
`available to these patients. Of 200 patients (95% of
`whom had bone metastases), 37% received chemo-
`therapy, with the remaining 63% receiving only ste-
`roids and supportive care (14).
`Chin et al. (16) performed a retrospective chart
`review of 88 patients with CRPC in secondary care
`who received docetaxel as a first-line chemotherapy.
`Of these, 36 patients (41%) progressed to require a
`second-line chemotherapy agent. Third-line therapy
`was used by eight patients (9%) and fourth-line in
`one patient (1%).
`On entry to the observational health-related qual-
`ity of life study described earlier (19), the treatments
`used by 280 patients with metastatic CRPC were
`reported to include bone-seeking radioisotope (8%
`of patients), external beam therapy of prostate or
`prostate bed (9%),
`transurethral resection of
`the
`prostate ⁄ laser ablation of prostate (14%) and other
`external beam therapy (44%). Docetaxel was the
`most commonly used chemotherapeutic agent used
`before baseline (7% of patients).
`The therapeutic choices for patients in the end
`stages of disease reported in a separate study were
`quite different. Hwang et al. reported the hospital
`resources used by 87 patients with CRPC in the last
`6 months of life (18). In total, 49% of the patients
`had received radiation for symptom palliation and
`52% received physical therapy. Opioids were pre-
`scribed to 90% of patients in the last 6 months of
`life. Three studies reported the palliative therapy
`administered to patients with bone pain or other
`
`Table 5 CRPC in numbers
`
`skeletal events (13–15). The most common therapies
`used were radiotherapy, radionuclide therapy, bis-
`phosphonates and opioids.
`
`Discussion
`
`Summary of results
`Data from retrospective and prospective observa-
`tional studies involving a total of 71,179 patients
`observed for up to 12 years demonstrate that CRPC
`is associated with frequent bone metastases, reduced
`survival and a poor quality of life (Table 5). The epi-
`demiologic data described here add to and comple-
`ment the body of evidence from controlled clinical
`trial settings (21). Data from a study of 200 patients
`with CRPC revealed that only 37% of patients
`received chemotherapy, with the remaining 63%
`receiving only steroids and supportive care, perhaps
`an indicator of the limited treatment options for
`patients with CRPC (14).
`
`Disease progression
`
`Progression to CRPC
`Our study identified five papers that evaluated the
`prevalence of CRPC in patients with prostate cancer.
`Estimates of
`the proportion of prostate
`cancer
`patients who develop CRPC varied from 9.5% overall
`to 53% within 5 years of follow-up from diagnosis
`(10,20). However, when we consider only those stud-
`ies that defined CRPC in terms of a rise in PSA lev-
`els following castration,
`the prevalence is in the
`range from 10% to 20% over an approximate 5-year
`period. However, the data in the included studies do
`not allow a thorough evaluation of time-to-castra-
`tion-resistance after the initiation of androgen sup-
`pression, or factors, such as metastases and treatment
`pathway, which may influence this. The results of
`our review do suggest that the prevalence is similar
`in those who have undergone prostatectomy and
`those who have not, and a previous study has also
`reported that prior prostatectomy does not confer a
`survival advantage in men with CRPC (22). How-
`ever, further epidemiological research into the impact
`of disease stage at time of castration and treatment
`paradigm is required.
`
`Prevalence
`
`Metastases
`
`Survival
`
`10–20% of prostate cancer patients develop CRPC within
`approximately 5 years of follow-up
`‡ 84% of patients have metastases present at the time of CRP