©TheCanadian Journal ofUrology™: International Supplement, April 2014
The phase III placebo controlled trial randomized
922 men with symptomatic bone-metastatic CRPC
using a 2:1 ratio to receive six injections every 4weeks
of either radium 223 (50 kBq/kg) or placebo.
32
Entry
criteria included at least two bonemetastaseswithout
visceralmetastasesandeitherpriordocetaxel treatment
or inability to receivedocetaxel. Theprimaryendpoint
wasoverall survival,with secondaryendpointsof time
to first SRE, time to alkaline phosphatase progression,
alkaline-phosphatase response, alkaline-phosphatase
normalization, time-to-PSA-progression, safety, and
quality-of-life. Thestudywasdesignedwith90%power
todetectahazardratiofordeathof0.76at5%significance
level. The trialwas halted at interim analysis after 809
patients (541 on radium 223 and 268 on placebo) had
been randomized. The twoarmswerewellbalanced in
termsofbaselinedemographics.Atinterimanalysis,50%
of thepatients receiving radium223had receivedall six
injectionsincomparisonto35%ofplacebowhile21%and
19%werestillundergoingtherapy. Mediansurvivalwas
significantly increased from11.2months to14.0months
withahazard ratioof 0.695 in favorof radium223.
Subsetanalysisrevealedthatthesurvivaladvantage
was primarily seen in those patients who had not
previously received docetaxel (hazard ratio 0.611;
95%CI: 0.423-0.883) as opposed to those who had
receiveddocetaxel (hazard ratio 0.755; 95%CI: 0.565-
1.009) and those with ECOG performance of 0-1
(hazard ratio 0.691; 95%CI: 0.535-0.892) as opposed
to thosewith a score ≥ 2 (hazard ratio 0.731; 95%CI:
0.398-1.343). Use of concurrent bisphosphonate did
not impact the survival advantage. Inaddition, there
was significant improvement inmedian time to SRE
(13.6 months versus 8.4 months), time to alkaline
phosphataseprogression,and time toPSAprogression
(hazard ratio 0.671) favoring the treatment arm.
Adverseevents(AEs)weredeterminedforanyman
who received> 1 injection in 762patients. AEswere
observed in 88% of the radium 223 patients and 94%
of placebo-treatedpatients. SeriousAEswerehigher
in theplacebogroup (43%versus55%) and treatment
discontinuationdue toAEswashigher in theplacebo
group (13% versus 20%). Grade 3/4 hematologic
toxicities were comparable between the two arms
(neutropenia 3% versus 1%, thrombocytopenia 6%
versus2%,anemia13%versus13%). Nonhematologic
Grade 3/4 toxicities included bone pain (21% versus
26%), nausea (2% in either cohort), diarrhea (2%
in either cohort), vomiting (2% in either cohort),
fatigue (5% versus 6%), and bone pain (21% versus
26%). A statistically higher percentage of patients
hadmeaningful improvement in quality-of-lifewith
radium 223over placebo.
Assessment andmanagement
Prior to initiation of radium 223 therapy, baseline
hematologic evaluationmust be performed at which
theabsoluteneutrophil count (ANC) shouldbe≥1.5x
10
9
/L, platelet count of ≥100x10
9
/L, andhemoglobin
≥ 50 x 10
9
/L. Before subsequent treatments, theANC
shouldbe≥1x10
9
/L,andplateletcountof≥50x10
9
/L.
If recovery to the values mentioned above does not
occurwithin6 to8weeksafteradministration, despite
supportive care, radium 223 should be discontinued.
Further, inpatientswith life threateningcomplications
frombonemarrowfailureshouldhave their treatments
halted.
Given, thatradium223 isexcretedvia the intestinal
system, which can manifest as diarrhea, nausea
or vomiting, careful monitoring of the patient’s
oral intake and fluid status is crucial to prevent
dehydration. There are no contact restrictions for
patients receiving radium 223 and patients are
instructed to follow good hygiene during the 6
months of therapy and 1 week after completion
of treatment to minimize radiation exposure to
householdmembers and caregivers.
Futuredirections
Radium 223 is the first radiopharmaceutical to
provide a prolongation in overall survival in men
with castration resistant prostate cancer. The safety
profile of radium 223 is encouraging, in comparison
to the
β
emitters, which may allow for increased
dosing (phase I study planned), integration with
myelosuppressive chemotherapy (NCT01106352,
phase I/IIa study of safety and efficacy of radium
223with docetaxel in patientswith bonemetastasis
from castration resistant prostate cancer), or novel
AR targeting agents (phase I study planned with
enzalutamideandabirateroneacetate). The long term
safetydataof radium223arestillunknownandareof
particular importancewhen considering integration
of thisagent in thesettingofnon-metastaticormicro-
metastatic disease especially in terms of potential
secondarymalignancy. However, thisagentprovides
another beacon of hope in the management of this
disease.
Disclosure
Dr. Robert B. Den is a speaker for the Bayer Algeta
OncologySpeakerBureau.
Dr. Karen E. Knudsen and Laura A. Doyle have no
potential conflict of interest.
74
Practical guide to theuseof radium 223dichloride
