©TheCanadian Journal ofUrology™: International Supplement, April 2014
Materials andmethods
Asystematicliteraturereviewwasconductedviaelectronic
database searchesofPubMed/Medline. Searcheswere
conductedwiththefollowingcombinationsanditeration
ofthefollowingterms:castrationresistantprostatecancer,
castration resistant, CRPC, prostate cancer, androgen
resistance, hormone-refractory, hormone-independent,
androgenreceptor,androgenreceptoraxis. Articleswere
selectedbasedontitle,abstract,studyformat,andcontent
bya consensusof theauthors. Themajorityof selected
articleswerepublishedbetween 1992 and 2013. Older
studieswere included selectively ifhistorically relevant
or incaseof scantydata inmore recentpublications.
Results
Changes in the spectrum of advanced prostate
cancer clinical presentation
The rate of patients with locally advanced (clinical
T3/4NX/+M0) andmetastaticprostatecancerat time
of presentation has declined since the introduction
of prostate-specific antigen (PSA). Nevertheless,
these men contribute disproportionately to prostate
cancer mortality and morbidity from this disease.
PSA screening has also led to a change in clinical
presentationofthesepatients.Whilepatientspresented
with local symptomsdue to locallyadvanceddisease
or cachexia, fatigueandbonepain in thepre-PSAera,
PSA screening led to diagnosis of locally advanced
prostate cancer inasymptomaticpatients. Ithasbeen
recognized that inpatientswithnoevidenceof nodal
ormetastatic disease, reliance on theT stage alone to
define locallyadvanceddiseaseandriskgroupswithin
it isnot sufficient.
8
Therefore inclusionof pretherapy
clinical andpathologicparameters other than clinical
T stage such as PSAandGleason score have led to a
broaderdefinitionof locallyadvanceddiseaseandare
used to identifymen at high risk for prostate cancer
progression.
8,9
Similarlyas topatientsat timeofpresentation,PSA
has launchedanew“clinical state“ forCRPCaswell,
namely patients with or without clinical metastases,
who have an increasing level of PSA despite ADT,
but noobvious signs of progressionbasedon clinical
criteria or available imagingmodalities.
10
Metastatic
CRPC has a poor prognosiswith amean survival of
16-18months.
11
Anemergingclinicalphenomenon isthefindingthat
up to 25%ofmenwith late stageprostate cancer have
a neuroendocrine phenotype.
12
Poorly differentiated
neuroendocrineprostatecancer(smallcellcarcinomaof
theprostate) isanaggressivediseaseand is frequently
accompanied by presence of visceral metastases.
Neuroendocrine tumors lack AR, do not secrete
PSA and show poor response to androgen ablation.
While neuroendocrine prostate cancer as a primary
diagnosis is rare, neuroendocrine differentiation of
prostatecancer increaseswithdiseaseprogressionand
in response toADT,
13
which is likely due to selective
treatment pressures driving the tumor to become less
reliantonsignaling throughAR. This is therapeutically
problematicandmandatesfindingnewmechanismsfor
tumorgrowth inhibition.
New definitions of castration resistant and
metastaticCRPC
With the demonstration of prostate cancer shrinkage
viahormone therapy in1941, thefoundationswere laid
foranewdisease,namelycastrationresistantprostate
cancer.
14
New insights intomechanisms of prostate
cancer resistance to ADT over the last two decades
have led to revised terminologies of thisdisease.
Despite initial response to hormone therapy, the
majority of patients with advanced prostate cancer
will progresswithin
amedian of 2 to 3 years
from
the start of ADT.
15
Prostate cancer cells survive
and resume growth despite ADT via adaptation to
androgen-depletedconditionsandalternativesurvival
andgrowthpathways.
16,17
This state of disease was widely referred to as
hormone-refractoryprostatecancer. The termsuggests
that furtherhormonal treatmentof theprostatecancer
will not beuseful.
In 1982, Fowler and Whitmore observed that
administration of testosterone led to unfavorable
responses especially in those patients who were in
symptomatic relapse following endocrine therapy.
18
These results indicated that although the prostate
cancer was progressing despite ADT, it was still
responding to androgen action and therefore not
independent of or refractory to androgens.
Different additional hormonal therapy strategies
includingmaximumandrogenblockade,antiandrogen
withdrawal, variation of specifc antiandrogens
(e.g. bicalutamide, flutamide, nilutamide), estrogen
compounds (diethylsilbestrol), adrenal suppressants
(ketoconazole) haveprovenhelpful.
Recognizing that the term hormone-refractory
was used heterogeneously in a broad spectrum of
prostate cancer patients, in 1999 Scher et al proposed
a refinement of the classification of patients with
relapsingdiseasedespiteADT.
19
Theauthorsreviewed
19 trialsofrelapsedpatientsunderADTandfound that
onlyone includedadefinition forhormone-refractory
diseasebasedonat least twovaluesofelevatedPSA.
19
8
Thechanging landscapeofadvancedandcastrationresistantprostatecancer: latestscienceandreviseddefinitions
