See discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/51717470
`
`Characterising the castration-resistant
`prostate cancer population: a systematic
`review. Int J Clin Pract
`
`ARTICLE in INTERNATIONAL JOURNAL OF CLINICAL PRACTICE · NOVEMBER 2011
`
`pac Fac o : 2.54 DO : 0.
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`/j. 742 24 .20
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`.02799.x Sou ce: PubMed
`
`C A ONS
`58
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`83
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`V EWS
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`3 AUTHORS, INCLUDING:
`
`Mike Kirby
`University of Hertfordshire
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`126 PUBL CA ONS 1,438 C A ONS
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`SEE PROF LE
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`Avai ab e o : Mike Ki by
`Re ieved o : 4 Sep e be 20 5
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`

`

`S Y S T E M A T I C R E V I E W
`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
`
`1180
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`doi: 10.1111/j.1742 1241.2011.02799.x
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`The Epidemiology of CRPC
`
`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
`
`ª 2011 Blackwell Publishing Ltd Int J Clin Pract, November 2011, 65, 11, 1180 1192
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`1182
`
`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).
`
`ª 2011 Blackwell Publishing Ltd Int J Clin Pract, November 2011, 65, 11, 1180 1192
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`

`The Epidemiology of CRPC
`
`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 naıve 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
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`1184
`
`The Epidemiology of CRPC
`
`undergoneRP
`PCwhohave
`19%ofpatentswth
`
`months
`Medan55(range1–145)
`
`PCnsecondarycare
`53%ofpatentswth
`
`55months
`Medan
`
`wthPC
`112%ofpatents
`
`Upto10years
`
`patentswthPC
`95%ofcastrate
`
`25months
`fromdatabase,mean
`Fooweduntext
`
`patentswthPC
`178%ofcastrate
`
`Upto6years
`
`ncreasngtrend
`
`SerumPSA>04ng⁄mwthan
`aesononaCTscan
`esononabonescanorgrowthof
`durngandrogendeprvaton,anew
`twoconsecutvencreasesnPSA
`Desptecastrateevesoftestosterone,
`
`ofncreasngevesofPSA
`castratonandtemporaevdence
`Arecordofmedcaorsurgca
`orchemotherapy
`toathrdhormonatherapy
`second-nehormonetreatment
`definedasaswtchfromther
`postcastratonhormonetherapy,
`patentswhofaedtorespondto
`CRPCstatuswasassgnedto
`scoreofmutpefactors
`dentfiedusngapropensty
`patentswthCRPCwere
`castratonFurthermore,
`foowngsurgca⁄medca
`AteasttwoncreasesnPSA
`
`47–87)years
`Medan70(range
`
`tay(1996–2003)
`
`atndexdate
`40yearsormore
`
`wereanaysed)
`1998to2008
`UK(recordsfrom
`
`18–97years
`
`wereanaysed)
`2000to2008
`USA(recordsfrom
`
`atndexdate
`40yearsormore
`
`wereanaysed)
`2001to2007
`USA(recordsfrom
`
`PrevaenceofCRPC
`
`Foow-upperod
`
`DefintonofCRPC
`
`Patentage
`
`conducted)
`(yearsstudy
`Country
`
`CRPC,castraton-resstantprostatecancer;CT,computedtomography;NR,notreported;PC,prostatecancer;PSA,prostate-specficantgen;RP,radcaprostatectomy
`
`NR
`
`USA(1990–1999)
`
`undergoneRP
`PCwhohad
`1045patentswth
`
`Banco(12)
`
`hadRP
`wthPCwho
`Patents
`
`nsecondarycare
`dagnosedwthPC
`211patentsnewy
`caredatabase
`aUKprmary
`PCusngdatafrom
`8678patentswth
`Retrospectvestudyof
`camsdatabase
`medcacare
`dentfiedfromaUS
`undergonecastraton,
`wthPCwhohad
`44,791patents
`Retrospectvestudyof
`
`camsdatabase
`aUSmedcacare
`patentswthPCfrom
`datafrom15,361
`Retrospectvestudyof
`
`sampe
`Study
`
`Berrut(10)
`
`Morgan(11)
`
`Cabrera(20)
`
`Aemayehu(9)
`
`Reference
`
`wthPC
`Patents
`
`Table1TheprevalenceofCRPCinpatientsprostatecancer
`
`ª 2011 Blackwell Publishing Ltd Int J Clin Pract, November 2011, 65, 11, 1180 1192
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`

`The Epidemiology of CRPC
`
`1185
`
`CRPC,castraton-resstantprostatecancer;CT,computedtomography;EOD,extentofdsease;NR,notreported;PSA,prostate-specficantgen
`
`atstartofstudy
`73(range66–80)
`
`(1999–2002)
`NR
`
`CRPC
`201patentswth
`
`Smth(17)
`
`73(range52–92)
`
`(1990–2003)
`tay
`
`CRPCnsecondarycare
`200patentswth
`
`Berrut(14)
`
`33%at2years
`
`48months
`
`NA
`
`0%
`
`95%hadboneesons
`definedasEODscore‡1
`Bonemetastass
`
`37%
`
`therapy
`androgen-deprvaton
`RsngPSAdespte
`ofaesononaCTscan
`onabonescanorgrowth
`deprvaton,aneweson
`nPSAdurngandrogen
`Twoconsecutvencreases
`castraton
`undersurgca⁄medca
`ant-androgentherapy
`nPSAaftercombned
`
`84%
`
`NR
`
`Threeconsecutvencreases
`
`metastases
`presenceofbone
`Progressonto
`
`perod
`Foow-up
`
`dagnossofCRPC
`metastasesat
`ofbone
`Prevaence
`
`chemotherapy
`whoreceved
`patents
`Percentageof
`
`ofCRPC
`Definton
`
`(years)
`atCRPCdagnoss
`Meanage
`
`conducted)
`(yearsstudy
`Country
`
`44%wereage70–79
`26%wereage60–69
`
`(1990–2004)
`Japan
`
`wthCRPC
`151patents
`
`sampe
`Study
`
`noue(13)
`
`Reference
`
`Table2Prevalenceofbonemetastases
`
`ª 2011 Blackwell Publishing Ltd Int J Clin Pract, November 2011, 65, 11, 1180 1192
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`1186
`
`The Epidemiology of CRPC
`
`dagnoss(n=81)
`wthoutbonepanat
`monthsnthose
`comparedwth30
`CRPCwas18months
`panatdagnossof
`65patentswthbone
`Medansurvvanthe
`
`dagnossofCRPC
`145monthsfrom
`Medansurvvawas
`
`dagnossofCRPC
`06–67)from
`13months(range
`Medansurvvawas
`
`ofCRPC
`fromdagnoss
`86±106months
`Meansurvvawas
`
`Survva
`
`andfromCRPCdagnoss18months
`ntaPCdagnoss43months
`
`NR
`
`Meanfoow-upperodfrom
`
`37%
`
`14%
`
`(18monthafteratestenroment)
`untdeathorastfoow-up
`FromdocumentatonofCRPC
`
`ofCRPCuntdeath
`Fromdocumentaton
`
`23%
`
`chemotherapy
`whoreceved
`patents
`Percentageof
`
`NR
`
`perod
`Foow-up
`
`castraton
`surgca⁄medca
`therapyunder
`ant-androgen
`aftercombned
`ncreasesnPSA
`Threeconsecutve
`onaCTscan
`growthofaeson
`onabonescanor
`deprvaton,aneweson
`PSAdurngandrogen
`consecutvencreasesn
`testosterone,two
`Desptecastrateevesof
`
`hormonetherapy
`scanwherecevng
`esonsbyboneorCT
`
`Worsenngmetastatc
`scntgraphy
`metastasesonbone
`actvtyandappearanceof
`rsngakanephosphatse
`serumPSAconcentraton,
`bonepan,rsng
`Progressveyworsenng
`
`44%wereage70–79
`26%wereage60–69
`
`(1990–2004)
`Japan
`
`wthCRPC
`151patents
`
`noue(13)
`
`73(range52–92)
`
`(1990–2003)
`tay
`
`nsecondarycare
`
`200patentswthCRPC
`
`Berrut(14)
`
`73(range52–96)
`
`(1994–1999)
`USA
`
`nsecondarycare
`wthCRPC
`patents
`cohortof89
`Retrospectve
`
`Hwang(18)
`
`ª 2011 Blackwell Publishing Ltd Int J Clin Pract, November 2011, 65, 11, 1180 1192
`
`NR
`
`(NR)
`Netherands
`
`ofCRPC
`Definton
`
`dagnoss(years)
`atCRPC
`Meanage
`
`conducted)
`(yearsstudy
`Country
`
`nsecondarycare
`wthCRPC
`84patents
`
`sampe
`Study
`
`(15)
`Soerdjbae-Makoe
`
`Reference
`
`Table3SurvivalinpatientswithCRPC
`
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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,castraton-resstantprostatecancer;CT,computedtomography;NR,notreported;PSA,prostate-specficantgen
`
`dagnoss
`foowngaCRPC
`fromfirstchemotherapy
`(range124–205)months
`Medansurvvawas159
`
`Survva
`
`100%
`
`UntFebruary2008
`
`oftestosterone
`desptecastrateeves
`symptomatcprogresson
`ncreasngPSAevesor
`
`chemotherapy
`whoreceved
`patents
`Percentageof
`
`perod
`Foow-up
`
`ofCRPC
`Definton
`
`Medan71years
`
`dagnoss(years)
`atCRPC
`Meanage
`
`2005–June2007)
`(August
`Canada
`
`nsecondarycare
`wthCRPC
`88patents
`
`conducted)
`(yearsstudy
`Country
`
`sampe
`Study
`
`Chn(16)
`
`Reference
`
`Table3Continued
`
`ª 2011 Blackwell Publishing Ltd Int J Clin Pract, November 2011, 65, 11, 1180 1192
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`

`

`1188
`
`The Epidemiology of CRPC
`
`appetteoss
`vomtng,dyspnoeaand
`domanswerepan,nauseaand
`thestudyperodThemostsenstve
`andsgnficantdeteroratonover
`ofthosenEORTCshowedarapd
`questonnares,andthemajorty
`theFACT-PandtheEQ-5D
`HRQoLsymptomsassessedn
`
`12%
`
`9months
`
`monthsafterdagnoss
`compresson3days–10
`24%deveopedspnacord
`
`23%
`
`NR
`
`durngthefoow-upperod
`89%experencedbonepan
`foow-upperod
`bonefracturesdurngthe
`bonepanand14%experenced
`dagnoss80%experenced
`panattmeofCRPC
`45%experencedbone
`
`Outcome
`
`37%
`
`18months
`
`NR
`
`fromCRPCdagnoss
`Mean18months
`
`chemotherapy
`receved
`patentswho
`Percentageof
`
`perod
`Foow-up
`
`byTNMstagngcrtera
`M1metastatcCRPCwas
`Dagnossofsymptomatc
`onbonescntgraphy
`appearanceofmetastases
`phosphatseactvtyand
`concentraton,rsngakane
`pan,rsngserumPSA
`Progressveyworsenngbone
`growthofaesononaCTscan
`esononabonescanor
`androgendeprvaton,anew
`ncreasesnPSAdurng
`testosterone,twoconsecutve
`Desptecastrateevesof
`
`castraton
`therapyundersurgca⁄medca
`combnedant-androgen
`ncreasesnPSAafter
`
`Threeconsecutve
`
`FunctonaAssessmentofCancerTherapy-Prostate;HRQoL,heath-reatedquatyof
`CRPC,castraton-resstantprostatecancer;CT,computedtomography;EORTC,EuropeanOrganzatonforResearchandTreatmentofCancerQuatyofLfe;EQ-5D,5-dmensonEuroQoquestonnare;FACT-P,
`
`fe;NR,notreported;PSA,prostate-specficantgen;TNM,TumourNodeMetastass
`
`72years
`
`Mutnatona(NR)
`
`metastatcCRPC
`280patentswth
`
`Suvan(19)
`
`NR
`
`TheNetherands(NR)
`
`73(range52–92)
`
`tay(1990–2003)
`
`age70–79
`44%were
`age60–69
`26%were
`
`Japan(1990–2004)
`
`ofCRPC
`Definton
`
`(years)
`atCRPCdagnoss
`Meanage
`
`conducted)
`(yearsstudy
`Country
`
`secondarycare
`wthCRPCn
`84patents
`
`secondarycare
`wthCRPCn
`200patents
`
`wthCRPC
`151patents
`
`sampe
`Study
`
`Soerdjbae-Makoe(15)
`
`Berrut(14)
`
`noue(13)
`
`Reference
`
`Table4SymptomsandqualityoflifeinpatientswithCRPC
`
`ª 2011 Blackwell Publishing Ltd Int J Clin Pract, November 2011, 65, 11, 1180 1192
`
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`

`

`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