©TheCanadian Journal ofUrology™: International Supplement, April 2014
78
Practical guide to theuseof chemotherapy in castration resistant prostate cancer
TABLE 1.
Docetaxel basedphase III trials
Study
Treatment
Objective
PSA %with Time to Survival
regimen
measurable
response palliative progression (months)
response rate (%) rate (%) response
SWOG 9916 Docetaxel/estramustine
17
50
17*
6
18
Mitoxantrone/prednisone
10
27
11
3
16
TAX 327 Docetaxel (q 3wks)/prednisone 12*
45
35
7.9*
18.9
Docetaxel (qwk)/prednisone 8*
48
31
8.2*
17.4
Mitoxantrone/prednisone
7*
32
22
7.8*
16.5
*didnot reach statistical significance
Figure1.
StudydesignsofSWOG99-16andTAX327.
treatments. Historically, chemotherapy for advanced
prostate cancer was viewed as toxic and ineffective.
Two reviews of single agent cytotoxic therapy inmen
with CRPC demonstrated that objective responses to
chemotherapywere6.5%to8.7%,withno improvement
in survival.
3,4
The combination of mitoxantrone-
prednisone was approved by the Food and Drug
Administration (FDA)basedonpalliationofbonepain;
three randomized trials also demonstrated modest
improvementsintimetoprogressionwhenmitoxantrone
combined with corticosteroids was compared to
corticosteroidsalone.
5-7
Until2004,CRPCwasconsidered
a chemotherapy resistant diseasewith no randomized
studydemonstratingasurvival of chemotherapy.
Docetaxel forCRPC
A semisynthetic taxane derived from the needles of
Taxusbaccata
,docetaxel. Docetaxelreversiblystabilizes
microtubules and prevents depolymerization.
8
Apoptosisresults fromaccumulationofmicrotubules,
aswellas throughphosphorylationofanoncoprotein,
Bcl-2.
9
Both invitroand invivostudiesfounddocetaxel
tobeeffectiveagainstawiderangeofhumancancercell
lines, including theprostate cancer cell linesDU 145,
PC-3andLNCaP.
10,11
Phase I and II trialsofdocetaxel
administeredasasingleagentor incombinationwith
estramustine phosphate demonstrated PSA decline
ratesof>50% in36%-69%of treatedpatients,objective
response rates of 17%-38% and median survivals
of 20-23 months.
12-15
Two phase III trials compared
docetaxel-basedcombinationregimenswithstandard
mitoxantrone/prednisone in men with progressive
CRPC, Figure 1 andTable 1.
TAX327 was an international multi-center study
that compared two different dosing schedules of
docetaxel/prednisonewithmitoxantrone/prednisone
for metastatic CRPC.
16
No history of any prior
chemotherapy in theseCRPCpatientswaspermitted
except for estramustine. One thousand six patients
wererandomized tooneof threearms: 1)docetaxel75
mg/m
2
every3weeks;docetaxel30mg/m
2
weekly for
5of6weeksormitoxantrone12mg/m
2
every3weeks.
Prednisone at 5mg PO bidwas given to all patients
at 5mgPOBID.
Themediansurvivalwassuperior tomitoxantrone
only in the3weekdocetaxel arm (18.9monthsversus
16.4 months) (p = 0.009). Weekly docetaxel did not
result in a statistically significant survival advantage
(17.4 months versus 16.4 months, p = 0.36). When
compared to themitoxantrone/prednisonegroup, the
reduction in the riskofdeathwas24%and9% for the
every3weekandweeklydocetaxelarms, respectively.
Anupdatedsurvivalanalysis found thatmorepatients
survived 3 years when treatedwith docetaxel either
every 3 weeks or weekly (18.6% and 16.6%when
compared to mitoxantrone (13.5%).
17
PSA declines
of > 50%were significantly higher (45% and 48%) in
patients treated on the 3week andweeklydocetaxel
groups, respectively, than in thepatients treatedwith
mitoxantrone (32%). No significant differences in
